CN1989244A

CN1989244A - Inhibitors of tgf-r signaling for treatment of cns disorders

Info

Publication number: CN1989244A
Application number: CNA2005800098901A
Authority: CN
Inventors: 巫利希·柏格丹; 路德威·艾格纳; 法兰克·彼得·华什斯; 贝亚特·温纳; 尤尔根·温克勒
Original assignee: REGENION GmbH
Current assignee: Lu Dewei; You Li
Priority date: 2004-02-09
Filing date: 2005-02-09
Publication date: 2007-06-27
Anticipated expiration: 2025-02-09
Also published as: BRPI0507528A; WO2005074981A8; WO2005074981A2; IL177320A; ZA200606460B; AU2005210151B2; JP2007521815A; IL177320A0; US20110263678A1; JP4712728B2; CA2555463C; EP1716235B1; AU2005210151A1; RU2385933C2; PL1716235T3; EP1716235A2; NZ548926A; WO2005074981A3; US8283334B2; KR100880371B1

Abstract

The present invention relates to the use of oligonucleotides for the preparation of a pharmaceutical composition for the prevention or treatment of a disease, wherein neurogenesis and/or neuroregeneration has a beneficial effect, in particular a disease like Morbus Alzheimer, Morbus Parkinson, Lewy Body Dementia,-Amyotrophic Lateral Sclerosis, Spinocerebellar Atrophies, Creutzfeldt Jakob Disease, Frontemporal Dementia, Morbus Pick, AIDS Dementia Complex, Vascular Dementia, Progressive Supranuclear Palsy, Corticobasal Degeneration, Multisystem-Atrophy, Hallervorden Spatz Disease, Huntington's disease, Stroke, Traumatic Brain and spinal cord Injury, Retinitis Pigmentosa, Macular Degeneration, Glaucoma, Cochlea Degeneration, Depression, Schizophrenia, Multiple Sclerosis, and developmental neurodegeneration.

Description

The TGF-R signal that is used for the treatment of the CNS illness transmits inhibitor

Technical field

The present invention relates to oligonucleotide and be used to prepare that prevention or treatment are wherein neural takes place and/or neurotization has the purposes of medical composition of the disease of beneficial effect, described disease is neurodegenerative disease especially, as Alzheimer's disease (Alzheimer ' s disease), Parkinson's disease (Parkinson ' sdisease) (comprise multiple system atrophy (Multisystem Atrophy)), ophthalmic nerve nuclear paralysis disease on the carrying out property, cortex basal nuclei degeneration disease, dementia with Lewy body disease, amyotrophic lateral sclerosis (Amyotrophic Lateral Sclerosis) and other motor neuron diseases, Huntington's disease (Huntington ' s disease), spinocerebellum atrophy (SpinocerebellarAtrophy, SCA), storehouse Jia Shi disease (Creutzfeldt Jakob disease, CJD) and other serious prion diseases, Frontemporal Dementia (Frontemporal Dementia) (comprising Pick's disease), aids dementia complex, HallervordenSpatz Disease (Haliervorden Spatz disease), Huntington's disease, cerebrovascular disease (as vascular dementia), apoplexy, traumatic cerebral and Spinal injury, retinitis pigmentosa, macular degeneration, glaucoma, dysthymia disorders and schizophrenia and expansionary illness (for example Down's syndrome (Down ' s syndrome)).

Background technology

Many serious nerve degeneration illnesss have the serious social economic influence to modern society, for example as following each sick illness: Alzheimer's disease, follow dull-witted expansionary illness (for example Down's syndrome), Parkinson's disease, dementia with Lewy body disease, Frontemporal Dementia, Pick's disease, amyotrophic lateral sclerosis, the spinocerebellum atrophy, storehouse Jia Shi disease, aids dementia complex, vascular dementia, ophthalmic nerve nuclear paralysis disease on the carrying out property, cortex basal nuclei degeneration disease, multiple system atrophy, Huntington's disease, apoplexy, traumatic brain injury, retinitis pigmentosa, macular degeneration, glaucoma, dysthymia disorders, schizophrenia and multiple sclerosis.Common pathology physiology cause is found in heredity, give birth to the back or acquired defective in, it causes the gathering of cell debris to form or accumulation usually, finally causes carrying out sexual disorder, and causes neuronal cell at last or spongiocyte is dead and structure is disintegrated.Staticly around microgliacyte and the blood vessel hugely have a liking for cell, attempt scavenger cell and fragment of tissue through attracting and activation.This may take place in extremely short time span, as in the Jia Shi disease of storehouse, perhaps goes through and takes place decades, as in Parkinson's disease or multiple sclerosis.Activated microgliacyte/huge is had a liking for cell colony and discharge a large amount of inflammatory cytokines in extracellular matrix, thereby it is drained in Venule or the CSF space.Unfortunately, the nerve that can have advantageous effect (and no matter which kind of its individual specificity's pathophysiological mechanism is) to the clinical onset course of disease of above-mentioned disease takes place and neurotization is subjected to unknown so far machine-processed the inhibition.Therefore, the technical problem that the present invention is basic be to provide by disturb neural take place and the inhibition of neurotization to be suitable for treating or the prevent nerve degeneration illness or to be the means of the symptom relevant at least with described illness.

Summary of the invention

The embodiment that the solution of described technical problem characterizes by providing in claims is achieved.Known TGF-'beta ' family albumen, be that TGF-β 1, TGF-β 2 and TGF-β 3 and specific cell surface receptor TGF RI thereof, TGF RII, TGF RIII play a role at some critical aspects of embryo, and mainly be that development at mesenchymal cell/neural top layer (neuroektodermal) organ plays a role.This makes embryonic stem cell be divided into the neurone precursor cell, and has neuroprotective for injured mature neuron.Further known its differentiation has keying action to hemopoietic stem cell, thereby control propagation and differentiation.At the experimental session that the present invention carried out, find TGF-R, be that TGF R1 and TGF RII relate to the key factor in suppressing neural generation and neurotization, and therefore can disturb this bioactive compound of TGF R or TGF RII to can be used for treatment/prevention nerve degeneration illness and/or neural inflammatory conditions.

The experimental result that the present invention carried out is summarized as follows:

1., identify the physiological regulating control circulation that causes effective CNS regeneration level by precursor cell/stem cell although individual component is known (TGF-β, TGF-RII, celiolymph compartment, vitreum, endolymph fluid, neurone precursor cell etc.).This circulation is to cause the reason of closing neurotization in most of CNS pathology, and wherein the crucial target molecule TGF-RII of round-robin expresses in ventricle wall.

2. regulation and control that interesting is not are to take place via blood, lymph or extracellular matrix, but via taking place with neuronal cell and precursor cell thereof or the direct fluid in contact compartment of stem cell (celiolymph etc.).

3. find that neurone/oligodendroglia (oligodendroglial) or starlike regenerated physiology suppress circulation for repairing the dreamboat of the strategy that damages in the CNS, it can significantly be used for the nearly all destructive pathology of neural system.According to previous knowledge about TGF-β; more would rather attempt increasing but not reduction (referring to 5) TGF-β function, so that increase its known neuroprotective or immunosuppressive activity in CNS: our supposition is here transmitted by the TGF-RII signal of blocking ventricle wall and is reduced its inhibit feature for stem cell regenerating.

4. although infer for a long time that inflammatory process plays an important role in nerve degeneration, and a large amount of relatively clinical preceding and clinical datas shows supports described idea, but disclose major cycle now, it makes all separately metacyclic combinations harmoniously of regulation and control, for example cytokine (IL-1, IL-6, IL-12) and other.

5. in addition, should notice that Nature has preferentially proposed the preferential CNS of immunity in neuroprotective and the neurotization.Showed that so far immunity is preferential and not enough in neurotization through the CNS of highly protection (attacking and Neuron Apoptosis to avoid immunity through special protection); this is definite because this is preferential and because same molecular TGF-β; wherein because the TGF-beta system, so this immunity CNS preferential and through highly protecting is an integral part.As if the evolution notion help adhering to acute neuroprotective and the most of sophisticated functions thereof of high complexity CNS; In this article, as if individual neurotization is lower than the importance of individual neuroprotective for evolving.

The regulation and control circulation

The neural generation of the physiology of brain allows by precursor cell continuous repair out of the ordinary/replacement fault or aging neurone, oligodendroglia or stellate cell.The neurotization that is used for the brain reparation is to regulate and control through celiolymph by TGF-β-TGF-R (especially TGF RII also is TGF RI) system; Main cooperation is to produce TGF-β and via extracellular space it is secreted microgliacyte to CSF (and in vitreum, endolymph) compartment and neurone precursor cell/stem cell/huge and have a liking for cell line cell, and it is by receiving this signal at the TGF-RII or the TGF-RI of great expression on its surface tissue or ependyma lining form with same receptor via CSF (and in vitreum, endolymph).In most of CNS pathology, the neural generation through badly damaged or break down.Regulate neurogenetic regulation and control, normally have a liking for cell and suppress by activate microgliacyte/huge in CNS, it betides in the pathological situation of any specified disease.Have a liking for the regeneration that cell suppresses nerve degeneration, acute and chronic inflammatory, anoxic, atherosclerosis or aging brain soft tissue by this approach institute activatory microgliacyte/huge, described approach is CSF to ventricle district/other neural generating area down.Not only neurone differentiation is affected, and oligodendroglia and stellate cell system also are affected.To disturb this circulation to advocate to be treatment to improve all molecules of neurone/oligodendroglia/stellate cell regenerated.It also is considerable adopting the method for described round-robin diagnosis, prophylactic treatment (prophylaxis), prevention (prevention) or forecast CNS pathology, and it is used for the effect that monitor treatment is intervened convincingly.

In above-mentioned illness, the protein aggregation body in artery sclerosis or acute wound/anoxic dependency necrocytosis, cell debris, inflammation, Inflammatory response attract microgliacyte and the potential blood vessel static huge cell of having a liking on every side.This can be acute, subacute or chronic process.In reactivation process, activated microgliacyte colony (comprise from vessel wall or other sources huge and have a liking for cell) is released into a large amount of inflammatory cytokines in the extracellular matrix, drains into it in Venule or directly drains in the CSF space.These cytokines will arrive the CSF compartment, and can use in all positions immediately, and these positions are TGF-β by CSF around these cytokines to a certain extent.Verified (Monje, M.L, people such as H.Toda, (2003). " Inflammatory blockade restores adulthippocampal neurogenesis. " Science 302 (5651): 1760-1765) neural inflammation suppresses neural generation, and carry out the inflammatory blocking-up with common non-steroidal anti-inflammatory drug thing INDOMETHACIN (indomethacin) and after the inflammation of endotaxin induction, recover neural the generation, and after the skull irradiation, increase neural the generation.

Yet prior art does not disclose the TGF-β as neural generation of downward modulation and the neural main adjusting control agent of repairing under injured back or the pathological conditions.On the contrary, prior art thinks that TGF-β avoids necrocytosis as neuroprotective prevention of injuries or injured neurons, and attempts raising the TGF-β in the CNS disease.

People such as Zhang (Zhang, J.M., people (1997) such as R.Hoffmann. " Mitogenic andantiproliferative signals for neural crest cells and the neurogenicaction of TGF-betal. " Dev.Dyn.208 (3): 375-386.) proof TGF-β influences developmental quail neural crest cell.Here TGF-β suppresses multipotency neural crest cell (and/or its direct derivative) and loyal melanocytic propagation, thereby causes reducing of group's size.In addition and opposite with the present invention, the neural generation significantly increases under the TGF-β existing.In the positive group of the neuroblast of handling through TGF-β, the number in the group of each suprarenin cell and secreted neural unit presoma increases.

TGF-β has vital role in cell growth and differentiation, allelotaxis, matrix formation, wound repair and immunologic function.Although TGF-β is effective growth-inhibiting substance of many cell types, it stimulates the propagation of fibroblast and sclerocyte.It also is the effective stimulus agent of being produced by the extracellular matrix that fibroblast and sclerocyte carry out, and suppresses substrate degradation, and raises the matrix phase mutual effect of acceptor.Pointed out that TGF-β 1 is the crucial origin cause of formation factor in the pathogeny of hepatic fibrosis, and be a kind of crucial conditioning agent of Ciclosporin A (cyclosporine A) at least the useful and deleterious effect of immunity system and kidney.In addition, showed that various chronic progressive external fibrosis kidney illnesss are relevant with the stimulation of TGF-beta system in human and the experimental model.

TGF-β 1 reduces G1 and G2 cyclin-dependent kinase and cyclin aspect kinase activity and protein content.TGF-β 1 also in the human marrow leukemia cell a plurality of Serines and threonine residues place be suppressed to the product phosphorylation of retinocytoma suppressor gene pRb.Underphosphorylated pRb is relevant with transcription factor E2F-4 in the G1 phase, and through the pRb of phosphorylation mainly in conjunction with E2F-1 and E2F-3.Because TGF-β 1 raises p130 (pRb family member)/E2F-4 complex body and forms, and downward modulation p107 (pRb family member)/E2F-4 complex body forms, wherein the E2F-4 level is kept constant, so these results' announcements are worked as cell and are left the cell cycle, and when being attracted by the effect of TGF-β 1, E2F-4 changes pRb and p130 into from p107." cdk inhibitor " p27 is the positive and the negative conditioning agent of the cell cycle control that mediated of TGF-β 1.Be the selected inhibitor of normal original hemopoietic stem cell although reported TGF-β 1, TGF-β all suppresses bone marrow leukemia cells original and differentiation more and is.What mainly pay close attention to is neuroprotective activity, its effect and effect in the regulation and control immune response thereof in neurodevelopment (neurodevelopmental) of TGF-β 1.Showed that in many researchs TGF-β 1 has neuroprotective in vitro and in vivo.Agonist research has proved the infarct size after TGF-β 1 reduces neuronal cell death and deutocerebrum obstruction of artery (MCAO); and on the contrary; the neuronal cell death of increase and the infarct size behind the MCAO have been showed in antagonist research, and this discloses TGF-β 1 and have neuroprotective in cerebral ischemia.Recently further indicated the neuroprotective effect of TGF-β 1 in cerebral ischemia about the research of TGF-β 1 overexpression that in vivo adenovirus mediated in the mouse, the reduction of exporting as neuronal cell death, infarct size and neuroscience proves.In addition, many in vitro researchs have proved that TGF-β 1 is from the neuroprotective ability in the multiple species neurone of (comprising rat, mouse, chicken and the mankind).Especially interesting is to show that 1 pair of various dead inductor/injury of TGF-β has protectiveness, comprises Hypoxia, glutaminate exitotoxicity, amyloid beta, oxidative damage and human immunity disappearance virus.The neuroprotective effect of TGF-β 1 is kept the mitochondrial membrane electromotive force, is stablized Ca with it ²⁺Running balance, increase inhibitor of apoptosis protein Bcl-2 express, suppress Casprotease-3 and activate relevant with the ability of inducing Profibrinolysin activator inhibitor-1 with Bcl-xl.The verified original neural stem cell of research in the embryonic stem cell is to be transmitted the component of the nervous system standard of institute's negative regulation by TGF-β dependency signal.The neural generation of endogenous expression positive regulation grownup that has shown another TGF family member TGF-α.TGF-α breeds fully by the progenitor cell that is present in subependymal layer and the neurone presoma that migrates to olfactory bulb produce fully essential.In TGF-α knock-out mice, the propagation of these progenitor cells also reduces along with the age, and this may be because the prolongation of cell cycle.Endogenous TGF-α old and feeble or lack do not influence in the presence of Urogastron in vitro the number of isolating neural stem cell.

TGF-β is used for immunoregulatory purposes and seriously is subjected to its toxic inhibition in the mankind, comprise overstimulation, Toxicity of Kidney and other deleterious effects that matrix produces.TGF-β has carcinogenic potential, and has been involved in glomerule ephrosis, lung fibrosis, scleroderma and the chronic transplant versus-host disease.In addition, although TGF-β is the very effective immunosuppressant cell factor, some evidences show that the chronic stimulation (in disease-related or the transgenic animal model) that TGF-β expresses can cause or strengthen the autoimmunity inflammation unreasonably.

Exist ever-increasing evidence proof in the pathologic, physiologic of various CNS pathology, to play a crucial role as the strong inflammatory properties of the TGF-β of the reverse conditioning agent of t cell immune response.Therefore, think that this cytokine is the potential target that injured dependency peptide and treatment are intervened.Neural inflammation is relevant with many sacred diseases with mesoglia pathology.Here the most classical obviously is the nerve immunity disease, for example multiple sclerosis.But it also comprises cognitive illnesses, wherein notable feature is the loss of memory, for example Alzheimer's disease, dementia with Lewy body disease, aids dementia complex, vascular dementia, perhaps loss of memory significance is less, for example ophthalmic nerve nuclear paralysis disease, cortex basal nuclei degeneration disease and storehouse Jia Shi disease on Pick's disease, the carrying out property.In addition, after the acute injury of for example apoplexy, traumatic brain and Spinal injury, activate the inflammatory program.In the different animals model of storehouse Jia Shi disease, reported the rise (Baker of microglial activation and TGF-β 1, C.A., people (1999) such as Z.Y.Lu. " Microglialactivation varies in different models of Creutzfeldt-Jakob disease. " J Virol 73 (6): 5089-5097).

In hundreds of different nerve degeneration illnesss, only pay close attention to a few, comprise Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.It should be noted that identical nerve degeneration process can influence the different zones of brain, make that to see institute on symptom position very different to disease.The nerve degeneration illness of central nervous system (CNS) can be divided into pallium disease (Alzheimer's disease), basal ganglia disease (Parkinson's disease), brain stem and little disease of brain or diseases of spinal cord (amyotrophic lateral sclerosis).

The example of nerve degeneration and nerve degeneration illness is: Alzheimer's disease, Parkinson's disease, storehouse Jia Shi disease (CJD), the neomorph of storehouse Jia Shi disease (new variant of Creutzfeldt Jakobsdisease, nvCJD), HallervordenSpatz Disease, Huntington's disease, multiple system atrophy, dull-witted, Frontemporal Dementia, the motor neuron illness, amyotrophic lateral sclerosis, spinal muscular atrophy (Spinal Muscular Atrophy), spinocerebellum atrophy (SCA), schizophrenia, affective disorder, severe melancholia (major depression), meningoencephalitis (meningoencephalitis), bacillary meningoencephalitis, viral meningoencephalitis, the CNS autoimmune disorder, multiple sclerosis (Multiple Sclerosis, MS), acute ischemic/anoxia-induced apoptosis (acute ischemic/hypoxic lesion), the CNS wound, injury of head, arteriosclerosis, arteriosclerosis, microangiopathy dementia (microangiopathic dementia), binswanger (Binswanger ' disease), leukoaraiosis (Leukoaraiosis), retinal degeneration (retinal degeneration), cochlea degeneration (cochlear degeneration), macular degeneration (macular degeneration), cochlear deafness (cochlear deafness), acquired immune deficiency syndrome (AIDS) AIDS dependency dementia (AIDS-related dementia), retinitis pigmentosa (retinitis pigmentosa), vulnerability X-dependency is trembled/ataxia syndromes (fragileX-associated tremor/ataxia syndrome, FXTAS), ophthalmic nerve nuclear paralysis disease (progressive supranuclear palsy on the carrying out property, PSP), striatonigral degeneration (striatonigral degeneration, SND), Nux Canarii albi pon cerebellum degeneration disease (olivopontocerebellar degeneration, OPCD), shy dilatory person's syndromes (ShyDrager syndrome, SDS).

Influence the level of TGF-β 1

Raise TGF-β 1 and effect thereof

For neuroprotective or immunomodulatory purpose, many researchs attempt to increase TGF-β 1 level.Agonist research has proved the infarct size after TGF-β 1 reduces neuronal cell death and deutocerebrum obstruction of artery (MCAO); and on the contrary; the neuronal cell death of increase and the infarct size behind the MCAO have been showed in antagonist research, and this discloses TGF-β 1 and have neuroprotective in cerebral ischemia.Recently further indicated the neuroprotective effect of TGF-β 1 in cerebral ischemia about the research of TGF-β 1 overexpression that in vivo adenovirus mediated in the mouse, the reduction of exporting as neuronal cell death, infarct size and neuroscience proves.In addition, many in vitro researchs have proved that TGF-β 1 is from the neuroprotective ability in the multiple species neurone of (comprising rat, mouse, chicken and the mankind).Especially interesting is to show that 1 pair of various dead inductor/injury of TGF β has protectiveness, comprises Hypoxia, glutaminate exitotoxicity, amyloid beta, oxidative damage and human immunity disappearance virus.The neuroprotective effect of TGF-β 1 is kept the mitochondrial membrane electromotive force, is stablized Ca with it ²⁺Running balance, the expression that increases inhibitor of apoptosis protein Bcl-2 and Bcl-xl, inhibition Casprotease-3 activate relevant with the ability of inducing Profibrinolysin activator inhibitor-1.

Our main discovery is that it is the main molecule of oppositely regulating that mainly the CNS stem cell is repaired at physiology with in nearly all CNS pathology to the consistent TGF-β described in the provide protection of above-mentioned CNS: by TGF-β (responding to disease) that microgliacyte produced with low physiological level or higher level by cell in matrix leak out among the CSF.It can contain potential other location that progenitor cells layer region under the epidermis or CNS stem cell upgrade, in precursor cell/stem cell colony of CNS free and directly with through highly regulation and control and the TGF-RII that expresses and TGF-RI interaction.Described discovery is made up of retroregulation, and it causes the low stem cell under high CSF-TGF-β level to upgrade, and vice versa.Unusual and be significantly, the high expression level of TGF-RII and activity are to be positioned at precursor cell/stem cell colony propagation site, are SVZ or hippocampus in our experiment.The unusual signal that also has transmits via buffered soln, for example celiolymph (CSF).Therefore it is to regulate and control circulation fully, and wherein physiology is very similar with the pathology regulation and control, but difference only is intensity (in other words: TGF-β level among the CSF and the TGF-R expression level in the target cell).Individual nosopathology is phenotypic to be characterized as described different the change, as hereditary defect (for example multisystem synapsin disease, superoxide-dismutase sudden change (Superoxide Dismutase Mutation), trinucleotide repeat illness (Trinucleotide Repeat Disorder)) or wound, anoxic, vascular disease or inflammation, or CNS is aging.Yet; the executive of disease pathology always microgliacyte/huge has a liking for the TGF-β that cell colony produces: on the one hand; it has neuroprotective and inhibitive ability of immunity, helps progressively to demote to the acute inflammation damage of soft tissue and the neuron loss that may be caused by disease pathology.Just as two-sided god slave's Si head (Janus Head), same molecular prevents CNS to carry out injury repairing by disturb TGF-β-TGF-R ring on precursor cell or stem cell level by self stem cell/precursor cell indirectly, and then significantly suppresses stem cells hyperplasia.In this case, stem cell be not only derive from CNS those cells of the precursor cell in should considering, and convincing ground is also for attempting to invade from marrow blood vessel separately stem cell/the precursor cell of CNS soft tissue.This is also meaning and is passing through the simple TGF-β level in the soft tissue that reduces, and is deserved with elimination to neuroprotective/immunosuppressive action of CNS, thereby causes being damaged by the serious acute that inflammation and/or direct neural unit apoptosis cause.

Therefore as if the attraction approach for the stable intervention that helps repairing is only intervened in the part of TGF-R level, and do not jeopardize the beneficial effect of TGF-β to brain.Therefore, the present invention relates on the precursor cell/stem cell bank of expressing TGF-R, disturb the antisense oligonucleotide of the biologic activity of TGF-β 1.Described oligonucleotide or comprise medical composition at least a in the described oligonucleotide and can be used for diagnosing/prophylactic treatment/prevention or treatment be wherein neural to be taken place or neurotization has the disease of beneficial effect.As shown in our experiment, it also can be used for therapeutic prevention (for example after apoplexy or head injuries), should be effective before the described hereinafter mechanism.

Term used herein " disturbs (interfering) " and means adjusting, is preferably and reduces or elimination TGF-R and/or TGF-R _IIBiologic activity or its expression.Can (be preferably TGF-R by making compound and TGF-R _II) direct interaction or combination, perhaps by interacting (for example by interference and TGF-R and/or TGF-R indirectly _IIThe compound that biologic activity is relevant) realizes regulating biologic activity.For neurone/hemopoietic stem cell or the precursor cell that improves neurotization or increase CNS recovers (comprise all types of parts or general and transplant (for example in vitro breeding, allos cell)), serve as target TGF-β R _I,-R _II,-R _IIIOr its signal transduction is listed below with the suitable combination thing that disturbs described regulation and control round-robin medicament:

(a) plasmid, carrier or natural/synthetic/mutated viruses, has the oligonucleotide that all kinds modify (PTO for example, LNA, 2 ' F-ANA, albumen-Nucleotide complex body, RNAi, siRNA or mikromiRNA), the methyl methoxy base-, phosphoro-amidate, PNA, morpholinyl, phosphoramidate, tetrahydrobenzene (CeNA), between aggressiveness (gap-mere), ribozyme, aptamer (aptamer), the CpG-oligomer, the DNA-enzyme, examine switch (riboswitch) or lipid or contain lipid molecule

(b) peptide, peptide complex body comprise all types of connexons,

(c) cave in for a short time (caveoli) small numerator modified dose of Lipid Rafts (raft) or film,

(d) modifier of golgi body (golgi apparatus),

(e) antibody and derivative thereof, especially mosaic, Fab fragment, Fc fragment or

(f) carrier, liposome, nanoparticle, complex body or contain any other haulage system of above-mentioned appointment construct can be used for the above-mentioned circulation of target to recover or to improve neurotization.

Yet, most preferably antisense oligonucleotide in the above-mentioned medicament, this is because it early disturbs TGF-R or TGF-R period at the utmost point _IIFormation.The major advantage of these molecules is the target-specific that it is high, with and fabulous general and local tolerance; Its utmost point is suitable for being applied topically in the soft tissue or CSF space among the CNS.In addition, it is very stable, and therefore can easily use from the implanted suction system.It also significantly saves cost.

Therefore, in a preferred embodiment of the invention, can be used for disturbing coding TGF-R or TGF-R _IIThe compound of genetic expression be antisense oligonucleotide (antisense oligonucleotide).

The generation of suitable antisense oligonucleotide is included in TGF-R gene or TGF-R _IIBe identified for the site that antisense interacts and takes place in the gene, therefore can cause and to act on, for example inhibition of protein expression.The site is the zone that (a) comprises gene opening code-reading frame (ORF) transcription initiation or terminator codon in the preferred gene, and perhaps (b) is the mRNA zone of " ring " or " projection ", promptly is not the part secondary structure.In case identify one or more target sites, then select with target fully complementary (promptly fully hybridize and have enough specificitys) to produce the oligonucleotide that will act on.

Therefore, the present invention relates to have antisense oligonucleotide and the stand-in thereof that SEQ ID NO 1 or SEQ ID NO 2 or SEQ ID NO 94 or SEQ ID NO 95 or SEQ ID NO 96 comprise the subsequence of 8 to 50 nucleotide bases.Described oligonucleotide represent SEQ ID NO 12 or SEQ ID NO94 to 96 have the part of 8 to 50 nucleotide bases.In addition, the antisense oligonucleotide that comprises 8 to 50 nucleotide bases is not necessary for SEQ ID NO 1 or 2 or the accurate subsequence of SEQ ID NO 94 to 96.If antisense oligonucleotide be found in SEQ ID NO 12 or SEQ ID NO94 or 95 or 96 in subsequence have at least 80%, be preferably 84%, more preferably 88% and most preferably be 92% consistence, then it is enough.Preferred oligonucleotide has the consistent sequence of subsequence at least 80% that comprises 8 to 50 nucleotide bases with SEQ ID NO 1 or 2 or 94 or 95 or 96, wherein said sequence can with comprise coding TGF-R or TGF-R _IIThe gene opening code-reading frame transcription initiation or the zone of terminator codon or be " ring " or " projection " and be not the coding TGF-R or the TGF-R of part secondary structure _IIThe fully hybridization of mRNA zone.It means these antisense oligonucleotides has and coding TGF-R or TGF-R _IIThe corresponding zone at least 80% complementary sequence of gene, perhaps preferably have and (a) comprise coding TGF-R or TGF-R _IIGene opening code-reading frame transcription initiation or the zone of terminator codon, or (b) be the coding TGF-R or the TGF-R of " ring " or " projection " (promptly not being the part secondary structure) _IIMRNA zone at least 80% complementary sequence.

Preferably can with comprise coding TGF-R or TGF-R _IIGene opening code-reading frame transcription initiation or the zone of terminator codon, or be " ring " or " projection " and be not the coding TGF-R or the TGF-R of part secondary structure _IIMRNA zone fully hybridization have 8 to 50, be preferably the antisense oligonucleotide of 15 to 25 nucleotide bases.

The following extension sequence of SEQ ID NO 3 preferably, it can be represented by following general formula:

5′-XCAGCCCCCGACCCATGZ-3′

Wherein X is selected from the group that comprises following oligonucleotide:

ACAGGACGATGTGCAGCGGCCACAGGCCCCTGAG，

CAGGACGATGTGCAGCGGCCACAGGCCCCTGAG，

AGGACGATGTGCAGCGGCCACAGGCCCCTGAG，GGACGATGTGCAGCGGCCACAGGCCCCTGAG，

GACGATGTGCAGCGGCCACAGGCCCCTGAG，ACGATGTGCAGCGGCCACAGGCCCCTGAG，

CGATGTGCAGCGGCCACAGGCCCCTGAG，

GATGTGCAGCGGCCACAGGCCCCTGAG，

ATGTGCAGCGGCCACAGGCCCCTGAG，TGTGCAGCGGCCACAGGCCCCTGAG，

GTGCAGCGGCCACAGGCCCCTGAG，TGCAGCGGCCACAGGCCCCTGAG，

GCAGCGGCCACAGGCCCCTGAG，CAGCGGCCACAGGCCCCTGAG，

AGCGGCCACAGGCCCCTGAG，GCGGCCACAGGCCCCTGAG，

CGGCCACAGGCCCCTGAG，GGCCACAGGCCCCTGAG，

GCCACAGGCCCCTGAG，CCACAGGCCCCTGAG，CACAGGCCCCTGAG，

ACAGGCCCCTGAG，CAGGCCCCTGAG，AGGCCCCTGAG，

GGCCCCTGAG，GCCCCTGAG，CCCCTGAG，CCCTGAG，CCTGAG，CTGAG，TGAG，GAG，AG，G，

And wherein Z is selected from the group that comprises following oligonucleotide:

GCAGACCCCGCTGCTCGTCATAGACCGAGCCCCC，

GCAGACCCCGCTGCTCGTCATAGACCGAGCCCC，

GCAGACCCCGCTGCTCGTCATAGACCGAGCCC，GCAGACCCCGCTGCTCGTCATAGACCGAGCC，

GCAGACCCCGCTGCTCGTCATAGACCGAGC，

GCAGACCCCGCTGCTCGTCATAGACCGAG，

GCAGACCCCGCTGCTCGTCATAGACCGA，

GCAGACCCCGCTGCTCGTCATAGACCG，

GCAGACCCCGCTGCTCGTCATAGACC，GCAGACCCCGCTGCTCGTCATAGAC，

GCAGACCCCGCTGCTCGTCATAGA，GCAGACCCCGCTGCTCGTCATAG，

GCAGACCCCGCTGCTCGTCATA，GCAGACCCCGCTGCTCGTCAT，

GCAGACCCCGCTGCTCGTCA，GCAGACCCCGCTGCTCGTC，

GCAGACCCCGCTGCTCGT，GCAGACCCCGCTGCTCG，

GCAGACCCCGCTGCTC，GCAGACCCCGCTGCT，GCAGACCCCGCTGC，

GCAGACCCCGCTG，GCAGACCCCGCT，GCAGACCCCGC，

GCAGACCCCG，GCAGACCCC，GCAGACCC，GCAGACC，GCAGAC，GCAGA，GCAG，GCA，GC，G，

And wherein X and Z comprise together and are no more than 34 nucleotide bases and stand-in (mimetics) thereof.

More preferably following oligonucleotide sequence and variant or stand-in:

SEQ?ID?NO?3： 5′-CAGCCCCCGACCCATG-3′

SEQ?ID?NO?4： 5′-GCTGATGCCTGTCACTTGAA-3′

SEQ?ID?NO?5： 5′-GCCATGGAGTAGACATCGGT-3′

SEQ?ID?NO?6： 5′-GCAACAGCTATTGGGATGGT-3′

SEQ?ID?NO?7： 5′-GTGCAGGGGAAAGATGAAAA-3′

SEQ?ID?NO?8： 5′-GTATCAGCATGCCCTACGGT-3′

SEQ?ID?NO?9： 5′-GGATCCAGATTTTCCTGCAA-3′

SEQ?ID?NO?10： 5′-GGAGAAGCAGCATCTTCCAG-3′

SEQ?ID?NO?11： 5′-GAGCTCTTGAGGTCCCTGTG-3′

SEQ?ID?NO?12： 5′-GAGACCTTCCACCATCCAAA-3′

SEQ?ID?NO?13： 5′-TAGCTGGCTGTGAGACATGG-3′

SEQ?ID?NO?14： 5′-TTTTGAAACGCTGTGCTGAC-3′

SEQ?ID?NO?15： 5′-TCAGCCAGTATTGTTTCCCC-3′

SEQ?ID?NO?16： 5′-TCACACAGGCAGCAGGTTAG-3′

SEQ?ID?NO?17： 5′-TCAGGAATCTTCTCCTCCGA-3′

SEQ?ID?NO?18： 5′-TGGTAGTGTTTAGGGAGCCG-3′

SEQ?ID?NO?19： 5′-TATCCCCACAGCTTACAGGG-3′

SEQ?ID?NO?20： 5′-GCCTCTTTCCTCATGCAAA-3′

SEQ?ID?NO?21： 5′-TGTCATTTCCCAGAGCACC-3′

SEQ?ID?NO?22： 5′-AGGAATCTTCTCCTCCGAGC-3′

SEQ?ID?NO?23： 5′-AGCCATGGAGTAGACATCGG-3′

SEQ?ID?NO?24： 5′-ATGCTACTGCAGCCACACTG-3′

SEQ?ID?NO?25： 5′-CCTTCTCTGCTTGGTTCTGG-3′

SEQ?ID?NO?26： 5′-CCAGGAGAAATAAGGGCACA-3′

SEQ?ID?NO?27： 5′-CAGCAGCTCTGTGTTGTGGT-3′

SEQ?ID?NO?28： 5′-CCCACTGTTAGCCAGGTCAT-3′

SEQ?ID?NO?29： 5′-CAGCCCCCGACCCATGGCAGACCC-3′

SEQ?ID?NO?30： 5′-CAGCCCCCGACCCATGGCAGACC-3′

SEQ?ID?NO?31： 5′-CAGCCCCCGACCCATGGCAGAC-3′

SEQ?ID?NO?32： 5′-CAGCCCCCGACCCATGGCAGA-3′

SEQ?ID?NO?33： 5′-CAGCCCCCGACCCATGGCAG-3′

SEQ?ID?NO?34： 5′-CAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?35： 5′-CAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?36： 5′-CAGCCCCCGACCCATGG-3′

SEQ?ID?NO?37： 5′-GCAGCCCCCGACCCATGGCAGACC-3′

SEQ?ID?NO?38： 5′-GCAGCCCCCGACCCATGGCAGAC-3′

SEQ?ID?NO?39： 5′-GCAGCCCCCGACCCATGGCAGA-3′

SEQ?ID?NO?40： 5′-GCAGCCCCCGACCCATGGCAG-3′

SEQ?ID?NO?41： 5′-GCAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?42： 5′-GCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?43： 5′-GCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?44： 5′-GCAGCCCCCGACCCATG-3′

SEQ?ID?NO?45： 5′-AGCAGCCCCCGACCCATGGCAGAC-3′

SEQ?ID?NO?46： 5′-AGCAGCCCCCGACCCATGGCAGA-3′

SEQ?ID?NO?47： 5′-AGCAGCCCCCGACCCATGGCAG-3′

SEQ?ID?NO?48： 5′-AGCAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?49： 5′-AGCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?50： 5′-AGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?51： 5′-AGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?52： 5′-GAGCAGCCCCCGACCCATGGCAGA-3′

SEQ?ID?NO?53： 5′-GAGCAGCCCCCGACCCATGGCAG-3′

SEQ?ID?NO?54： 5′-GAGCAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?55： 5′-GAGCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?56： 5′-GAGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?57： 5′-GAGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?58： 5′-TGAGCAGCCCCCGACCCATGGCAG-3′

SEQ?ID?NO?59： 5′-TGAGCAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?60： 5′-TGAGCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?61： 5′-TGAGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?62： 5′-TGAGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?63： 5′-CTGAGCAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?64： 5′-CTGAGCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?65： 5′-CTGAGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?66： 5′-CTGAGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?67： 5′-CCTGAGCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?68： 5′-CCTGAGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?69： 5′-CCTGAGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?70： 5′-CCCTGAGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?71： 5′-CCCTGAGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?72： 5′-CCCCTGAGCAGCCCCCGACCCATG-3′。

Still more preferably following oligonucleotide sequence with and variant and stand-in:

SEQ?ID?NO?33： 5′-CAGCCCCCGACCCATGGCAG-3′

SEQ?ID?NO?34： 5′-CAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?35： 5′-CAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?36： 5′-CAGCCCCCGACCCATGG-3′

SEQ?ID?NO?41： 5′-GCAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?42： 5′-GCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?43： 5′-GCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?44： 5′-GCAGCCCCCGACCCATG-3′

SEQ?ID?NO?49： 5′-AGCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?50： 5′-AGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?51： 5′-AGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?56： 5′-GAGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?57： 5′-GAGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?62： 5′-TGAGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?73： 5′-ATGTGAAGATGGGCAAGACC-3′

SEQ?ID?NO?74： 5′-ATCTCCATGTGAAGATGGGC-3′

SEQ?ID?NO?75： 5′-AACGGCCTATCTCGAGGAAT-3′

SEQ?ID?NO?76： 5′-AACATCGTCGAGCAATTTCC-3′

SEQ?ID?NO?77： 5′-AATCCAACTCCTTTGCCCTT-3′

SEQ?ID?NO?78： 5′-AAACCTGAGCCAGAACCTGA-3′

SEQ?ID?NO?79： 5′-AGGGCGATCTAATGAAGGGT-3′

SEQ?ID?NO?80： 5′-AGTGCACAGAAAGGACCCAC-3′

SEQ?ID?NO?81： 5′-ACACTGGTCCAGCAATGACA-3′

SEQ?ID?NO?82： 5′-TTCCTGTTGACTGAGTTGCG-3′

SEQ?ID?NO?83： 5′-CACTCTGTGGTTTGGAGCAA-3′

SEQ?ID?NO?84： 5′-CAAGGCCAGGTGATGACTTT-3′

SEQ?ID?NO?85： 5′-CACACTGGTCCAGCAATGAC-3′

SEQ?ID?NO?86： 5′-CTGACACCAACCAGAGCTGA-3′

SEQ?ID?NO?87： 5′-CTCTGCCATCTGTTTGGGAT-3′

SEQ?ID?NO?88： 5′-TCAAAAAGGGATCCATGCTC-3′

SEQ?ID?NO?89： 5′-TGACACCAACCAGAGCTGAG-3′

SEQ?ID?NO?9O： 5′-TGATGCCTTCCTGTTGACTG-3′

SEQ?ID?NO?91： 5′-TTCCTGTTGACTGAGTTGCG-3′

SEQ?ID?NO?92： 5′-TTCTCCAAATCGACCTTTGC-3′

SEQ?ID?NO?93： 5′-GGAGAGTTCAGGCAAAGCTG-3′。

Exclude this purport claims category be following two known arrays: 5 '-GATCTTGACTGCCACTGTCTC-3 ' (J.Clin.Endocrinology﹠amp; Metabolism2003,88 (10), 4967-4976) and 5 '-(DevelopmentalBiology 1996,180,242-257) for CATGGCAGCCCCCGTC-3 '.

Especially preferred is sequence SEQ ID NO 3:5 '-CAGCCCCCGACCCATG-3 '.

Therefore, the present invention also relates to SEQ ID NO 3 to SEQ ID NO 93 in any one closely-related sequence.Described in this article sequence is called as " variant ".Can modify antisense oligonucleotide in many different ways.Can in main chain, modify, and be meant oligonucleotide, wherein between its nucleosides in the main chain phosphorus atom partially or completely replaced by other atoms.For instance, preferred modified oligonucleotides main chain comprises phosphorothionate, chirality phosphorothionate, two phosphorothionates, phosphotriester, aminoalkyl group phosphotriester, methyl-phosphonate, phosphinic acid ethyl ester and phosphonic acids C ₃-C ₁₀-alkyl ester, comprise 3 '-alkylene phosphonic acid ester and chiral phosphonate, phosphinate, phosphoramidate, comprise have 3 of normal 3 '-5 ' key '-amino phosphoramidate and aminoalkyl group phosphoramidate, thionic phosphoramidate, thionic phosphonate ester, thionic alkyl phosphotriester and boron substituted phosphate, its 2 '-5 ' analogue of being connected and the person that has the opposite polarity, wherein contiguous right nucleosides unit 3 '-5 ' to 5 '-3 ' or 2 '-5 ' to 5 '-2 ' connect.Also comprise various salt, mixing salt and free acid form.

Preferred also is the variant of SEQ ID NO 3 to SEQ ID NO 93, wherein at 3 ' end and/or at 1,2,3,4 or 5 other nucleotide base of 5 ' terminal interpolation.These other nucleotide bases are five nucleotide bases among the SEQ ID NO 1,2,94,95 or 96 preferably, and it directly occurred before or after sequence out of the ordinary.In addition, described preferred variants can have the exchange of 1,2,3 or 4 nucleotide base, and promptly in described preferred variants, one, two, three or four Nucleotide can replace through another nucleotide base.Should notice that these variants also can contain any modification of the disclosed main chain of this paper or base or sugar moieties, for example phosphorothionate main chain.

The preferred modified oligonucleotides main chain that does not comprise phosphorus atom in it has by key between short-chain alkyl or cycloalkyl nucleosides, mixes the formed main chain of key between heteroatoms and alkyl or cycloalkyl nucleosides.It comprises and has the morpholine base key main chain of (part is formed by the sugar moieties of nucleosides); Siloxane main chain; Sulfide, sulfoxide and sulfone main chain; First and second acyl groups (formacetyl) and the sulfo-first and second acyl group main chains; Methylene radical first and second acyl groups and the sulfo-first and second acyl group main chains; The main chain that contains alkene; The sulfamate main chain; Methylene radical imino-and methylene radical diazanyl main chain; Sulfonate and sulfonamide backbone; Amide backbone; The mixture of aforementioned type main chain; And other have N, O, S, P and the CH of mixing ₂The main chain of integral part.

Other preferred embodiments of the present invention comprise the oligonucleotide with phosphorothionate main chain or heteroatoms main chain, and especially have-CH ₂-NH-O-CH ₂-,-CH ₂-N (CH ₃)-O-CH ₂-(being known as methylene radical (methyl-imino) or MMI main chain) ,-CH ₂-O-N (CH ₃)-CH ₂-,-CH ₂-N (CH ₃)-N (CH ₃)-CH ₂-and-O-N (CH ₃)-CH ₂-CH ₂-(wherein the natural phosphodiester main chain is by-O-P-O-CH ₂-expression) oligonucleotide.The oligonucleotide that has morpholinyl part in the main chain or have the morpholinyl backbone structure or have an aminoalkylamide main chain also is preferred (vide infra).Oligonucleotide also can have sugared stand-in, and for example cyclobutyl moiety replaces penta furanose (pentofuranosyl sugar).

Hexanaphthene stand-in morpholinyl stand-in

B is meant can be further through deutero-alkali part, for example purine or pyrimidine group.

Another modification of oligonucleotide of the present invention comprises part or conjugate chemistry that one or more activity, cell distribution or cells that strengthens oligonucleotide are absorbed and is connected to oligonucleotide.Modified oligonucleotide also can contain one or more and be substituted or modified sugar moieties.Preferred oligonucleotide comprise in 2 ' position a kind of in the following group :-OH ,-F ,-the O-alkyl ,-the S-alkyl ,-the N-alkyl ,-the O-thiazolinyl ,-the S-thiazolinyl ,-the N-thiazolinyl ,-the O-alkynyl ,-the S-alkynyl ,-the N-alkynyl ,-O-alkyl-O-alkyl, wherein alkyl, thiazolinyl and alkynyl can be the C that is substituted or is unsubstituted ₁To C ₁₀Alkyl or C ₂To C ₁₀Thiazolinyl and C ₂To C ₁₀Alkynyl.Especially preferred modified sugar moieties is 2 '-O-methoxy ethyl sugar moieties (2 '-OCH ₂CH ₂OCH ₃, be also referred to as 2 '-O-(2-methoxy ethoxy) or 2 '-MOE) and 2 '-dimethylamino oxygen base oxethyl, for example O (CH ₂) ₂ON (CH ₃) (be known as 2 '-DMAOE).Especially preferred also is O[(CH ₂) _nO] _mCH ₃, O (CH ₂) _nOCH ₃, O (CH ₂) _nNH ₂, O (CH ₂) _nCH ₃, O (CH ₂) _nONH ₂, O (CH ₂) _nON[(CH ₂) _nCH ₃], wherein n and m are 1 to 10 integer independently of each other.Other preferably modify comprise 2 '-methoxyl group, 2 '-amino propoxy-and 2 '-fluorine.Other preferred oligonucleotide 2 ' position comprises a kind of in the following group :-OCH ₃,-OC ₂H ₅,-OC ₃H ₇,-O-ring-C ₃H ₅,-OCH (CH ₃) ₂,-OC (CH ₃) ₃,-OC ₄H ₉,-OPh ,-OCH ₂-Ph ,-NO ₂,-F ,-Cl ,-Br ,-I ,-N ₃,-CN ,-OCN ,-NCO ,-SCN ,-NCS ,-COCH ₃,-COC ₂H ₅,-COC ₃H ₇,-CO-ring-C ₃H ₅,-COCH (CH ₃) ₂,-CF ₃,-SH ,-SCH ₃,-SC ₂H ₅,-SC ₃H ₇,-S-ring-C ₃H ₅,-SOCH ₃,-SOC ₂H ₅,-SOC ₃H ₇,-SO-ring-C ₃H ₅,-SO ₂CH ₃,-SO ₂C ₂H ₅,-SO ₂C ₃H ₇,-SO ₂-ring-C ₃H ₅,-NH ₂,-NHCH ₃,-NHC ₂H ₅,-NHC ₃H ₇,-NH-ring-C ₃H ₅,-N (CH ₃) ₂,-N (C ₂H ₅) ₂,-N (C ₃H ₇) ₂,-N (ring-C ₃H ₅) ₂,-N[CH (CH ₃) ₂] 2-CH ₃,-C ₂H ₅,-C ₃H ₇,-CH (CH ₃) ₂,-C ₄H ₉,-CH ₂-CH (CH ₃) ₂,-CH (CH ₃)-C ₂H ₅,-C (CH ₃) ₃,-C ₅H ₁₁,-CH (CH ₃)-C ₃H ₇,-CH ₂-CH (CH ₃)-C ₂H ₅,-CH (CH ₃)-CH (CH ₃) ₂,-C (CH ₃) ₂-C ₂H ₅,-CH ₂-C (CH ₃) ₃,-CH (C ₂H ₅) ₂,-C ₂H ₄-CH (CH ₃) ₂,-C ₆H ₁₃,-C ₃H ₆-CH (CH ₃) ₂,-C ₂H ₄-CH (CH ₃)-C ₂H ₅,-CH (CH ₃)-C ₄H ₉,-CH ₂-CH (CH ₃)-C ₃H ₇,-C ₂H ₄-C (CH ₃) ₃,-CH (CH ₃)-CH ₂-CH (CH ₃) ₂,-CH (CH ₃)-CH (CH ₃)-C ₂H ₅,-CH ₂-CH (CH ₃)-CH (CH ₃) ₂,-CH ₂-C (CH ₃) ₂-C ₂H ₅,-C (CH ₃) ₂-C ₃H ₇,-C (CH ₃) ₂-CH (CH ₃) ₂,-CH (CH ₃)-C (CH ₃) ₃, C ₇-C ₁₀Alkyl, be substituted C ₁-C ₁₀Alkyl, alkylaryl, arylalkyl, O-C ₁-C ₁₀Alkyl, O-arylalkyl, Heterocyclylalkyl, Heterocyclylalkyl aryl, aminoalkyl group amino, poly-alkylamino, be substituted silylation, RNA leavings group, report group, insert son, be used to improve the group of the pharmacokinetics of oligonucleotide and/or drug effect characteristic or have the substituting group of similar characteristics.The deoxyribonucleotide base also is preferred.

Also can carry out similar modification, especially 3 of sugar ' position on 3 ' terminal nucleotide or in the 2-5 ' connection oligonucleotide, perhaps 5 of 5 ' terminal nucleotide ' position in other positions of Nucleotide.

Preferred modification can be represented by following structure fragment:

Wherein

R represents any above-mentioned substituting group of 2 ' position, and especially

-H、-F、-OH、-NH ₂、-OCH ₃、-OCH ₂CH ₂OCH ₃，

X and X ' be independently of each other-O-,-NH-,-S-,-CH ₂-and

Y represents-O ^-,-S ^-,-N (CH ₃) ₂,-OCH ₃,-SCH ₃

More preferably wherein X and X ' expression oxygen and Y represent the variant of sulphur.

In addition, pure diastereo-isomerism oligonucleotide or its stand-in or variant are preferred.Especially preferred is Sp-and Rp-diastereomer:

Rp diastereomer Sp diastereomer

Highly preferred also is sequence SEQ ID NO 3 to SEQ ID NO 93, and SEQ IDNO 3 especially, wherein has in the disclosed modification of this paper one or more.The phosphorothionate main chain partially or completely of the phosphorothionate in the main chain preferably, and in described phosphorothionate, Rp and Sp diastereomer are preferred.

Oligonucleotide of the present invention also can comprise nucleotide base and replace.Nucleotide base is four standard nucleotides bases adenine (A), thymus pyrimidine (T), guanine (C) and cytosine(Cyt) (G).Modified nucleotide base comprises other synthetic and natural nucleotide base, for example the 2-propyl group of the 6-methyl of 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, xanthoglobulin, 2-aminoadenine, VITAMIN B4 and guanine and other alkyl derivatives, VITAMIN B4 and guanine and other alkyl derivatives; Uridylic (U), 6-carboxyuracil, N ⁶-methyl-VITAMIN B4,5-halo uridylic, 5-halo cytosine(Cyt), 5-proyl uridylic, 5-proyl cytosine(Cyt), 6-azauracil, 6-azepine cytosine(Cyt), 6-azathymine, 5-uridylic (pseudouracil), 4-thiouracil; The 8-halo-, 8-amino-, the 8-thiol-, 8-sulfane base-, 8-hydroxyl-and other 8-substituted adenines and guanines; The 5-halo-, 5-bromo-, 5-trifluoromethyl-and other 5-substituted uracil and cytosine(Cyt)s especially; The 7-methyl guanine; 7-methyladenine, guanozola, 8-azaadenine, the assorted guanine of 7-denitrification, the assorted VITAMIN B4 of 7-denitrification, 3-deazaguanine purine and the assorted VITAMIN B4 of 3-denitrification, 2-thiouracil, 2-sulphur thymus pyrimidine and 2-sulphur cytosine(Cyt) etc., wherein 5-methylcytosine is substituted by preferably, and this is to modify increase nucleic acid duplex stability because shown these.

The variant that preferably has the sequence of any one among SEQ ID NO 3 to the SEQ ID NO 93, one of them, two, three or four nucleotide bases replace through other nucleotide bases or through the nucleotide base of chemically modified.Variant should refer to the sequence of SEQ ID NO 3 to SEQ ID NO 93, wherein for example one to four nucleotide base through uridylic (U), 5-halo uridylic, 5-methyl-cytosine(Cyt) and/or N ⁶-methyl-VITAMIN B4 replaces.Especially preferred is the variant of SEQ ID NO 3, one of them, two or three nucleotide bases replace through above-mentioned part.

" oligonucleotide " is meant the oligomer or the polymer of Yeast Nucleic Acid (RNA) or thymus nucleic acid (DNA) or its stand-in or variant.Described term comprises the oligonucleotide of being made up of (main chain) key between the nucleotide base of natural generation, sugar and covalency nucleosides and the non-natural with identity function produces oligonucleotide partly.Because desired characteristic, for example enhanced cell absorbs, enhanced nucleic acid target affinity and the stability that increases in the presence of nuclease, so described modified or be substituted oligonucleotide and be better than natural form usually.Though antisense oligonucleotide is the antisense compounds of preferred form, other oligomerization antisense compounds are contained in the present invention, including (but not limited to) for example hereinafter described oligonucleotide mimetic.Antisense compounds according to the present invention comprises about 8 to about 50 nucleotide bases (promptly about 8 nucleosides to about 50 connections), is preferably 9-42,10-36,11-32,12-30,13-28,14-26, and highly preferred be 15-25 nucleotide base.

Especially preferred antisense compounds is an antisense oligonucleotide, even more preferably comprises about 15 antisense oligonucleotides to about 25 nucleotide bases.

Antisense compounds comprises ribozyme, external guide sequence (EGS), oligonucleotide (few enzyme) and hybridizes in target nucleic acid and suppress other shot-catalysts RNA or the catalytic oligonucleotide of its expression.

Term " salt " is meant the physiology of compound (antisense oligonucleotide especially of the present invention) and/or pharmaceutically acceptable salt.By the formed pharmaceutically acceptable base addition salt of mineral alkali is alkali.The example of suitable organic and mineral alkali is for being derived from metal ion (for example aluminium), alkalimetal ion (for example sodium or potassium), alkaline-earth metal ions (for example calcium or magnesium) or amine salt ionic alkali or basic metal or alkaline earth metal hydroxides, carbonate or supercarbonate.Example comprises moisture LiOH, NaOH, KOH, NH ₄OH, salt of wormwood, ammonium hydrogencarbonate and sodium bicarbonate, ammonium salt; Primary amine, secondary amine and tertiary amine, for example hydroxide four alkane ammoniums; Than the low carbon number alkylamine, for example methylamine, TERTIARY BUTYL AMINE, PROCAINE HCL, PHARMA GRADE (procaine), thanomin; Aromatic yl alkyl amine, for example dibenzylamine and N, N-dibenzyl-ethylenediamin; Than low carbon number Alkylpiperidine, for example N-ethylpiperidine; Cycloalkyl amine, for example hexahydroaniline or dicyclohexyl amine; Morpholine; Glycosamine; The N-methyl-and N, N-dimethyl glycosamine; The 1-amantadine; Benzyl star (benzathine); Or derived from for example amino acid whose salt of arginine, Methionin, ornithine; Or the acid amides of natural neutrality or acidic amino acid; Chloroprocaine (chloroprocaine), choline, PROCAINE HCL, PHARMA GRADE or the like.

For the compound of the present invention of alkalescence can form pharmaceutically acceptable salt with organic acid and mineral acid.The example that is used for the appropriate acid of this acid salt formation is a hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, para-aminosalicylic acid, oxysuccinic acid, FUMARIC ACID TECH GRADE, succsinic acid, xitix, maleic acid, sulfonic acid, phosphonic acids, perchloric acid, nitric acid, formic acid, propionic acid, glyconic acid, lactic acid, tartrate, hydroxy-maleic acid, pyruvic acid, phenylacetic acid, phenylformic acid, para-amino benzoic acid, P-hydroxybenzoic acid, methylsulfonic acid, ethyl sulfonic acid, nitrous acid, ethylenehydrinsulfonic acid, vinyl sulfonic acid, tosic acid, naphthyl sulfonic acid, sulfanilic acid, camphorsulfonic acid (camphersulfonic acid), pottery acid (china acid), amygdalic acid, adjacent methyl-mandelic acid, hydrogen-Phenylsulfonic acid, picric acid, hexanodioic acid, D-o-tolyl tartrate, tartronic acid, α-toluic acid, (neighbour, between, to)-toluic acid, napthylamine sulfonic acid and known mineral acid of other one of ordinary skill in the art or carboxylic acid.In normal way by want sour contact ionization alkali form to prepare salt with capacity to produce salt.

Handle the salt free alkali form of regenerating with the suitable dilute alkaline aqueous solution of for example dilute sodium hydroxide, salt of wormwood, ammonium hydrogencarbonate and sodium bicarbonate aqueous solution.Free alkali form is different slightly on some physical properties (for example solvability in polar solvent) with its corresponding salt form, but for purposes of the present invention, described salt is equivalent to its corresponding free alkali form in addition.

Perhaps, medical composition of the present invention contains the carrier that allows to transcribe antisense oligonucleotide of the present invention (for example in mammalian hosts).This carrier is preferably the carrier that can be used for gene therapy.The preferred vector that can be used for gene therapy is a virus vector, for example adenovirus, baculovirus, simplexvirus, cowpox, perhaps more preferably RNA viruses, for example retrovirus.Retrovirus carrier even the derivative of murine or birds retrovirus more preferably.The example that can be used for described retrovirus carrier of the present invention is: Moloney murine leukemia virus (Moloneymurine leukemia virus, MoMuLV), Harvey murine sarcoma virus (Harvey murine sarcomavirus, HaMuSV), murine marrmary tumor virus (murine mammary tumor virus, MuMTV) and Rous sarcoma virus (Rous sarcoma virus, RSV).Most preferably, use non-human primate retrovirus carrier, for example (gibbon ape leukemiavirus GaLV), thereby provides with respect to murine carrier host range more widely gibbon ape leukemia virus.Because therefore recombinant retroviral enzymophathy poison defectiveness needs auxiliary to produce infected particle.For example, can provide so auxiliary by the auxiliary cell line that use contains in LTR the plasmid of all structure genes of coding retrovirus under regulating and controlling sequence control.Suitable helper is that one of ordinary skill in the art know.But described carrier can contain the gene of coding selective marker in addition, therefore can differentiate the cell through transduction.In addition, can make its mode that becomes target-specific modify the retrovirus carrier.For example, can realize this operation by the polynucleotide that insert coding sugar, glycolipid or albumen, are preferably antibody.The additive method of the known generation target-specific of one of ordinary skill in the art carrier.Be used in vitro or in vivo other suitable carriers of gene therapy and method are described in document and for known to the one of ordinary skill in the art; For example referring to WO 94/29469 or WO 97/00957.In order to reach the expression in the target organ (for example cerebral tissue) only, be used for the dna sequence dna that antisense oligonucleotide transcribes and be connected in tissue-specific promoter and be used for gene therapy.

In oligonucleotide structure, bound phosphate groups typically refers to main chain between the nucleosides that forms oligonucleotide.The normal key of RNA and DNA or main chain be 3 ' to 5 ' phosphodiester bond.The particular example that can be used for preferred antisense compounds of the present invention or variant comprises the oligonucleotide that contains key between modified main chain or non-natural nucleoside.Oligonucleotide with modified main chain comprises the oligonucleotide that does not have phosphorus atom in the oligonucleotide that keeps phosphorus atom in the main chain and the main chain.Can cause modified oligonucleotides main chain that stability increases for known to the one of ordinary skill in the art, described modification is preferably the phosphorothionate key or one or more bound phosphate groups (phosphate group) are replaced through phosphonic acid ester (phosphonic acids) group or through sulfuric ester (sulfuric acid) group or through sulphonate (sulfonic acid) group or through sulfoxide.Preferred oligonucleotide mimetic is to have showed the oligonucleotide mimetic with splendid hybridization characteristic, and is called as peptide nucleic acid(PNA) (PNA).In the PNA compound, main chain, especially the amino-ethyl glycine main chain of the sugar backbone of oligonucleotide through containing acid amides replaced.Keep nucleotide base, and it directly or indirectly is incorporated into the aza nitrogen atom of the amide moieties of main chain, and (for example referring to people such as Nielsen, Science 254 (1991), 1497-1500).

In the context of the present invention, " hybridization (hybridization) " means the hydrogen bonding between complementary nucleosides or the nucleotide base, its Ke Yi Wei Wo Sen-Ke Like (Watson-Crick), Hu Gesiting (Hoogsteen) or reverse Hu Gesiting hydrogen bonding.Term " complementary (complementary) " is meant accurate paired ability between two Nucleotide as used herein.For instance, if the Nucleotide of oligonucleotide specific location can with the Nucleotide hydrogen bonding at the same position place of DNA or RNA molecule, think that so oligonucleotide and DNA or RNA are complementary mutually in described position.When the correspondence position of capacity in each molecule was occupied by the Nucleotide of hydrogen bonding each other, oligonucleotide and DNA or RNA were complementary each other.Therefore, " but specific hybrid " and " complementation " is to be used to indicate the complementary of enough degree or accurately to match make that generation is stablized and specificity bonded term between oligonucleotide and DNA or RNA target.Affiliated field should be appreciated that the sequence of antisense compounds does not need and its target nucleic acid 100% complementation for the treatment of specific hybrid.The normal function that disturbs target DNA or RNA when combining of compound and target DNA or RNA molecule is when causing the effectiveness forfeiture, but the antisense compounds specific hybrid, and exist the complementarity of enough degree to combine the non-specific binding of (promptly under the situation that treatment is handled) under the required condition in specificity to avoid antisense compounds and non-target sequence.

In other preferred oligonucleotide mimetics, key between sugar and nucleosides (being the main chain of nucleotide units) is all replaced by novel group.Keeping the alkali unit is used for and suitably nucleic acid target compound hybridization.The example of having showed the described oligonucleotide mimetic with splendid hybridization characteristic is called as peptide nucleic acid(PNA) (PNA).In the PNA compound, the main chain of the sugar backbone of oligonucleotide through containing acid amides, especially replace through amino-ethyl glycine main chain.Keep nucleotide base, and it directly or indirectly is incorporated into the aza nitrogen atom of the amide moieties of main chain.

Another modification of oligonucleotide of the present invention comprises part or conjugate chemistry that one or more activity, cell distribution or cells that strengthens oligonucleotide are absorbed and is connected to oligonucleotide.Described part comprises lipid part, for example cholesterol moiety, cholic acid, thioether, hexyl-S-trityl mercaptan, sulfo-cholesterol, aliphatic chain (for example dodecanediol (dodecandiol) or undecyl residue), phosphatide (for example two hexadecyls-outer-glycerine (dihexadecyl-rac-glycerol) or triethyl ammonium-1,2-two-0-hexadecyl-outer-glycerine-3H-phosphonate), polyamine or polyglycol chain or adamantane acetic acid (adamantine acetic acid), palmityl part or octadecylamine or hexylamine base-carbonyl-oxygen base cholesterol moiety.The present invention also is included as the antisense compounds of chimeric compound.In the context of the present invention, " chimeric " antisense compounds or " mosaic " are to contain two or more chemically antisense compounds, especially oligonucleotide of different zones, each zone constitutes by at least one monomeric unit, promptly is Nucleotide under the situation of oligonucleotide compound.These oligonucleotide contain at least one zone usually, wherein oligonucleotide modified with the cell of giving resistance that oligonucleotide increases, increase to nuclease degradation absorb and/or increase to target nucleic acid in conjunction with affinity.The substrate of the enzyme that can shear RNA:DNA or RNA:RNA heterozygote can be served as in other zones of oligonucleotide.For instance.RNase H is a cellular endonuclease of shearing the RNA chain of RNA:DNA two zoariums.Therefore, the activation of RNase H causes the shearing of RNA target, and then the efficient that suppresses of the oligonucleotide of reinforcing gene expression greatly.Therefore, compare, when using chimeric oligonucleotide, use than short oligonucleotide and can obtain suitable result usually with the phosphorothionate deoxy-oligonucleotide of hybridizing in identical target region.Chimeric antisense compounds of the present invention can form the composite structure with two or more above-mentioned oligonucleotide, modified oligonucleotides, oligonucleoside and/or oligonucleotide mimetic.Also can be called heterozygote or gap body (gapmer) at compound described in the affiliated field.

The invention particularly relates to the purposes that the disclosed antisense oligonucleotide of this paper or its variant or stand-in are used for prophylactic treatment and treatment neurodegenerative illness, neural wound, neural blood vessel and neural inflammatory conditions (comprise and infect the back illness).Term " neurodegenerative illness and neural inflammatory conditions " is meant Alzheimer's disease, Parkinson's disease, storehouse Jia Shi disease (CJD), the neomorph (nvCJD) of storehouse Jia Shi disease, HallervordenSpatz Disease, Huntington's disease, multiple system atrophy, dull-witted, Frontemporal Dementia, the motor neuron illness, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellum atrophy (SCA), schizophrenia, affective disorder, the severe melancholia, meningoencephalitis, bacillary meningoencephalitis, viral meningoencephalitis, the CNS autoimmune disorder, multiple sclerosis (MS), acute ischemic/anoxia-induced apoptosis (comprising apoplexy), the CNS wound, injury of head, arteriosclerosis, arteriosclerosis, the microangiopathy dementia, binswanger, leukoaraiosis, retinal degeneration, cochlea is degenerated, macular degeneration, cochlear deafness, AIDS dependency dementia, retinitis pigmentosa, vulnerability X-dependency is trembled/ataxia syndromes (FXTAS), ophthalmic nerve nuclear paralysis disease (PSP) on the carrying out property, striatonigral degeneration (SND), Nux Canarii albi pon cerebellum degeneration disease (OPCD), shy dilatory person's syndromes (SDS).

More generally, the present invention relates to the disclosed antisense oligonucleotide of this paper or its variant or stand-in is used for the treatment of and TGF-R and/or TGF-R _IIRise or the enhanced signal purposes of transmitting (for example TGF-β) relevant disease by improving the standard.Antisense oligonucleotide and then inhibition TGF-R and/or TGF-R _IIExpression.Antisense compounds can replace antisense oligonucleotide to use, and perhaps can be used in combination with antisense oligonucleotide.Antisense compounds be meant this paper disclosed allow to transcribe the carrier of antisense oligonucleotide or be meant hybridize in coding TGF-R or TGF-R _IINuclease, external guide sequence (EGS), few enzyme (Oligozyme) and the shot-catalyst RNA or the catalytic oligonucleotide of target nucleic acid.Described antisense compounds suppresses TGF-R or TGF-R _IIExpression.Therefore, under described situation, existing TGF-R and/or TGF-R during the disease _IIAmount reduce.

The disclosed antisense oligonucleotide of this paper can be used for regeneration with antisense compounds and is connected the injured nerve path again and is used for the treatment of various neurodegenerative illnesss and neural inflammatory conditions with functional.

In another preferred embodiment of the present invention, can be used for disturbing TGF-R and/or TGF-R _IIThe compound of biologic activity be to reduce or suppress the compound that TGF-β 1 is incorporated into its acceptor.The preferred embodiment of these compounds is at TGF-beta receptor (referring to people such as Lin, 1992), preferred pin (neutralization) antibody to TGF-beta receptor II.Term " antibody " preferably relates to basically by the antibody that monoclonal antibody and unique monoclonal antibody formulation are formed that compiles with different epitope specificitys (epitopic specificity).Monoclonal antibody is by for example containing TGF-R or TGF-R by the known method of one of ordinary skill in the art _IIThe antigen of fragment or corresponding acceptor makes.As used herein term " antibody " (Ab) or " monoclonal antibody " (Mab) mean comprise can binding proteins specific complete molecule and antibody fragment (for example Fab and F (ab ') 2 fragments).Fab and F (ab ') 2 fragments lack the Fc fragment of complete antibody, remove from circulation quickly, and can have the non-specific tissue bond lower than complete antibody.(people such as Wahl., J.Nucl.Med.24:316-325 (1983)).Therefore, the product in these fragments and FAB or other immunoglobulin expression libraries is preferred.In addition, the antibody that can be used for the object of the invention comprises chimeric antibody, single-chain antibody and humanized antibody.

Being used for other preferred compounds of the present invention is soluble T GF-beta receptor.The fusion rotein of the Fc district that described soluble T GF beta receptor is an antibody and the cell foreign lands of TGF beta receptor.Described molecule has high affinity to soluble T GF-β 1.Therefore, the concentration of free TGF-β 1 sharply descends.According to the laboratory manual (R﹠amp of manufacturer; D Systems, Germany), human TGF-β R will encode _IIThe dna sequence dna of 159 amino-acid residue cell foreign lands (people such as Lin, Cell 1992,68 (4), 775-785) are blended in the Fc district of IgG 1, and express chimeric protein in mouse myeloma cell line NSO.

Term " solubility (soluble) " used in the context as this paper acceptor preferably relates to the receptor fragments that only comprises recipient cell foreign lands or its part, and it still can be in conjunction with its native ligand, and for example TGF-β 1.One of ordinary skill in the art can determine these fragments according to the known amino acid sequence of acceptor, and can determine the cell foreign lands of acceptor by using well-known process (for example by computer program (wetting ability mapping)).In the especially preferred embodiment of purposes of the present invention, described soluble T GF-beta receptor is TGF-beta receptor II.

The present invention also relates to be used for differentiate interference (a) TGF-R and/or TGF-R _IIBiologic activity or TGF-R and/or TGF-R _IIThe expression or (b) method of the compound that transmits of TGF-β 1/TGF-R signal, said method comprising the steps of:

(a) candidate compound is cultivated with the test macro that comprises TGF-β 1 and neurone precursor cell; With

(b) propagation of active TGF receptor expression of calibrating or neurone precursor cell; Wherein

(c) compare with the test macro that does not have described test compounds, (i) inhibition of active TGF expression of receptor or (ii) the disappearance indication of neurone precursor cell inhibition of proliferation have candidate compound with the characteristic of wanting.

The example of these candidate molecules comprises antibody, oligonucleotide, albumen (for example acceptor) or small molecules.Can design described molecule ideally with known technology.The described test macro that is used to screen preferably includes the material with similar chemistry and/or physical property, and described material most preferably is identical.Can be expression library by the compound that use preparation and differentiate according to the present invention, for example cDNA expression library, peptide, albumen, nucleic acid, antibody, little organic compound, part, hormone, peptide mimics, PNA or the like.Recently, WO 98/25146 describes and is used for screening the additive method that the complex body library has the compound of the characteristic of wanting, the described ability of wanting the especially short effect of characteristic, combination or antagonism polypeptide or its cell receptor.Complex body in the described library comprise the compound that is in test phase, record compound synthetic at least one step label and be subject to report the tethers (tether) of molecular modification.The modification of tethers is used to represent that complex body contains the compound with the characteristic of wanting.Can tag decoder to disclose at least one step of described compound in synthetic.For instance, differentiate with according to TGF-R of the present invention and/or TGF-R _IIOr the additive method of the interactional compound of nucleic acid molecule of the described molecule of encoding is in vitro to screen with the phage indicating system, and filters in conjunction with calibrating or with (for example) BIAcore equipment (Pharmacia) " in real time " measurement interaction.Can all these methods used according to the invention disturb TGF-R and/or TGF-R to differentiate _IIBiologic activity or the compound that transmits of described receptor expression or TGF β 1/TGF-R signal.

One of ordinary skill in the art also know can design, the stand-in of the little organic compound of substrate that synthetic and assessment (for example) can be served as the TGF beta receptor or part.For instance, the D-glucose stand-in of having described hapalosin are showed the similar efficient in the antagonism multi-drug resistance additional related albumen in cytotoxin to hapalosin; Referring to Dinh, J.Med.Chem.41 (1998), 981-987.The gene of coding TGF-β 1 or TGF-R also can serve as the target that is used to screen inhibitor.For instance, inhibitor can comprise in conjunction with coding TGF-R, be preferably TGF-R _IIThe albumen of mRNA of gene, and then make the native conformation instability of mRNA, and hinder and transcribe and/or translate.In addition, describe to differentiate the method for nucleic acid molecule in the document, for example simulated compound institute's bonded in cell has through definition or without the RNA fragment of the structure of definition target RNA molecule, it causes the delay of cell growth or necrocytosis; For example reach the reference of wherein being quoted referring to WO 98/18947.These nucleic acid molecule can be used to differentiate the interested unknown compound of medicine and pharmacology, and are used to differentiate the unknown RNA target that is used for the treatment of disease.These method and compositions can be used to differentiate the compound that can be used for reducing TGF-β 1 and/or corresponding receptor expression level.Can the method according to this invention test and the compound differentiated can be expression library, cDNA expression library, peptide, albumen, nucleic acid, antibody, little organic compound, hormone, peptide mimics, PNA or the like (Milner for example, Nature Medicine 1 (1995), 879-880; Hupp, Cell 83 (1995), 237-245; Gibbs, Cell 7 (1994), 193-198 and the reference of above being quoted).In addition, for example can use (for example) bring out with the insertion of the gene of the known targeting vector in affiliated field sudden change identifier number TGF-β 1 the supposition regulon gene and/or in TGF-β 1 upstream or the gene that plays a role of downstream.Described compound also can be the functional derivatives or the analogue of known inhibitor.For instance, described useful compound can be for handling the factor (transacting factor), and it is in conjunction with TGF-R or TGF-R _IIOr its regulating and controlling sequence of gene of encoding.Can differentiate with the standard method of affiliated field and handle the factor.In order to determine that albumen is self to be incorporated into albumen or regulating and controlling sequence, can carry out the analysis of standard natural rubber displacement body.In order to differentiate the processing factor that is incorporated into albumen or regulating and controlling sequence, albumen or regulating and controlling sequence can be as the affinity reagents in the standard protein purification method, perhaps as the probe that screens expression library.Also can realize identifier number and TGF-R or TGF-R _IIThe nucleic acid molecule of interactional polypeptide, for example (Science 274 (1996), TGF-β 1 described in 2063-2065) as Scofield by using so-called yeast " two-hybrid system ".In described system, TGF-β 1 is connected in the DNA of GAL4 transcription factor in conjunction with the territory.The yeast strain of expressing this fusion polypeptide and comprising the lacZ reporter gene that is driven by suitable promotor is blended in the vegetable-protein of activation domain or the cDNA library of its polypeptide transforms through expression, and described suitable promotor is discerned by the GAL4 transcription factor.Therefore, if by a kind of coded peptide among the described cDNA can with comprise (for example) TGF-R or TGF-R _IIThe fusogenic peptide of peptide interact, so described complex body can instruct the expression of reporter gene.For example, can be in this way with TGF-R or TGF-R _IIDifferentiate and TGF-R or TGF-R with the gene of each acceptor of coding _IIInteractional peptide and albumen.The obvious understanding of one of ordinary skill in the art can further be developed this and similar system to differentiate inhibitor.At last, the present invention relates to compound that method by mentioned earlier differentiates and be used to prepare that prevention or treatment are wherein neural takes place or neurotization has the purposes of medical composition of the disease of beneficial effect.The more detailed ground explain the present invention of following example.

The present invention also relates to differentiate the method for regulating the effect of institute's inductive treatment or prevention/prophylactic treatment by TGF-R-or TGF-RII-system at stem cell/precursor cell colony place.This may especially help to set up the successful treatment in the individual patient, thereby allows (for example) individually administration.Diagnostic method comprises

(a) use at TGF-R or TGF-RII and through the specificity nucleic (iodine, technetium, fluorine 18) of nuclear pharmaceuticals diagnostics or the general of specific antibody that is used for the rare earth element product/paramagnetism compound/iron particle mark of Magnetic resonance imaging through gadolinium salt, perfluoro-carbon or other.In this article, under the situation that does not have enough signal-to-noise ratios, must open the hemato encephalic barrier of subcuticle at once; Although this zone may enough be used for the visual of 3 Tesla machines through height vascularization and contrast gradient, open BBB and may be other help.This can carry out with intravenously hypertonicity solution (for example glycerine) or with VEGF (vascular endothelial growth factor).

(b) have the general of specific oligonucleotide (molecule same as described above) to use to TGF-R or TGF-RII: it can be through following mark:

Gd or ¹¹¹In-DTPH (5 ' XXXXXXXXXXXXXXXXX3 '-vitamin H)-(SA-OX 26,8D3 or Ak-HIR) (wherein Gd is used for MRI, ¹¹¹In is used for radiodiagnosis; OX 26 is used for mouse experiment and target mouse TfR, and 8D3 is a mouse anti rat TfR antibody, and AK-HIR is the antibody at human insulin's acceptor).These compounds can only hybridization and signal transmission in those cells of the active mRNA with TGF-R or TGF-RII.DTPH is as chelating construction agent, and Ak-HIR uses insulin receptor that oligonucleotide is shuttled back and forth in different barriers, and the latter is used to stride film and shuttles back and forth under the situation of TfR antibody.Have differentiated hybrid stability in these cells, wherein a large amount of mRNA can use, and therefore can detect significantly stronger signal (SusukiT, people such as Schlachetzki F, J.Nucl.Med.45:1766-1775,2004, Susuki T, Zhang Y, Zhang Y-f, Schlachetzki F, people such as Pardridge, Mol.Imaging 2005,3,356-363).

(c) (doublecortin DCX) has the general application (referring to WO2004067751) of specific oligonucleotide (molecule same as described above) to having two cortins as same tag in (b).

In medical composition, described above-claimed cpd preferably with the combination of pharmaceutically acceptable supporting agent." pharmaceutically acceptable (pharmaceutically acceptable) " means and contains any supporting agent, and it is the efficient of the biologic activity of interferon activity composition not, and the host's nontoxicity to being offerd medicine.The example of suitable medical supporting agent is known by affiliated technical field, and comprises phosphate buffered salt solution, water, emulsion (for example oil/water miscible liquid), various types of wetting agent, sterile solution etc.Can allocate described supporting agent with usual way, and can effective dose to person under inspection's active compound of offeing medicine." effective dose " thus be meant and be enough to influence disease process and seriousness causes the minimizing of described pathology or the amount of demulcent activeconstituents.Can determine to can be used for treating and/or preventing " effective dose " of these diseases or illness with the known method of one of ordinary skill in the art.Can realize the dispensing of suitable groups compound by different modes, for example by intravenously, intraperitoneal, subcutaneous, intramuscular, part or intracutaneous dispensing.Certainly, dosing way is decided on the kind of contained compound in the kind of therapy and the medical composition.In addition, compound of the present invention can form agent, receptor target molecule, solvent, sanitas and/or mixing diluents and dispensing with liposome, mixture.

Preferably infusion solution or solid substrate form be used for the pharmaceutical preparation that activeconstituents discharges continuously, it is in particular for the continuous release of at least a antisense oligonucleotide or its variant or stand-in.More preferably be suitable for the solution of topical administration in brain or the pharmaceutical preparation of solid substrate form.

Can determine dosage regimen by attending doctor and other clinical factors.Know as medical field, any patient's dosage is decided on many factors, comprises patient's the bodily form, body surface area, age, sex, the specific compound of being offerd medicine, dispensing time and approach, therapy kind, general health situation and the other drug of offeing medicine simultaneously.

The present invention relates to comprise the pharmaceutical preparation of at least a disclosed as mentioned oligonucleotide, its variant or stand-in.Replace or except that described at least a antisense oligonucleotide, can have at least a antisense compounds.Antisense compounds is meant to allow to transcribe the carrier of antisense oligonucleotide, the disclosed antisense oligonucleotide of especially a kind of this paper or be meant hybridizes in coding TGF-R or TGF-R _IINuclease, external guide sequence (EGS), few enzyme and the shot-catalyst RNA or the catalytic oligonucleotide of target nucleic acid.Described antisense compounds suppresses TGF-R or TGF-R _IIExpression, and be preferably and can reduce the TGF-R that forms or TGF-R respectively _IIAmount.

In a preferred embodiment of the invention, the disease that can be prevented and/or treated is neural inflammatory conditions, acute ischemia or the wound brain anoxic brain injury of nerve degeneration illness, CNS.The preferred embodiment of nerve degeneration or neural inflammatory conditions is an Alzheimer's disease, Parkinson's disease, storehouse Jia Shi disease (CJD), the neomorph (nvCJD) of storehouse Jia Shi disease, HallervordenSpatz Disease, Huntington's disease, multiple system atrophy, dull-witted, Frontemporal Dementia, the motor neuron illness, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellum atrophy (SCA), schizophrenia, affective disorder, the severe melancholia, meningoencephalitis, bacillary meningoencephalitis and viral meningoencephalitis (the inflammation retarded depression of prevention stem cells hyperplasia), CNS autoimmune disorder (as multiple sclerosis (MS)), acute ischemic/anoxia-induced apoptosis, the CNS wound, injury of head, arteriosclerosis, arteriosclerosis, the microangiopathy dementia, binswanger, leukoaraiosis, AIDS dependency dementia, vulnerability X-dependency is trembled/ataxia syndromes (FXTAS), ophthalmic nerve nuclear paralysis disease (PSP) on the carrying out property, striatonigral degeneration (SND), Nux Canarii albi pon cerebellum degeneration disease (OPCD), shy dilatory person's syndromes (SDS), retinal degeneration, macular degeneration, retinitis pigmentosa, cochlea is degenerated, cochlear deafness.Also can handle the age dependency minimizing (age dependant decrease) that stem cell upgrades.

Description of drawings

Fig. 1: TGF-β 1 suppresses the propagation of adult rodent neural stem cell and precursor cell

A) grow up rodent neural stem cell and precursor cell (NCS) culture through the recombinant human TGF-β of various concentration (0,5,10,50 nanograms/milliliter) 1 processing 7 days.At the 7th day, in hemocytometer, get rid of calibrating and come living cell counting by trypan blue.Data are expressed as the average cell number ± SD from three experiments carrying out in triplicate.B) effect of the neural precursor cell of 1 couple of human foetus of expression TGF-β.

Fig. 2: the effect of 1 couple of NCS of TGF-β is reversible

The rodent neural stem cell of growing up and precursor cell culture were handled 7 days through the human recombinant TGF-of 10 nanograms/milliliter β 1.At the 7th day, dissociated cell was got rid of calibrating by trypan blue and is counted, and inoculate the 1 pretreated cell through TGF-β under the situation that is with or without 10 nanograms/milliliter TGF-β 1.Carried out once described program in per 7 days.Data are expressed as the average cell number ± SD from three experiments carrying out in triplicate.

Fig. 3: the antibody of anti-TGF-beta RII can reduce the effect of 1 couple of adult rodent NCS of TGF-β

The rodent NSC culture of growing up exists or does not exist under the anti-TGF-beta RII antibody (10 mcg/ml) through the recombinant human TGF-of 10 nanograms/milliliter β 1 processing 7 days.At the 7th day, in hemocytometer, get rid of calibrating and come living cell counting by trypan blue.Data are expressed as the average cell number ± SD from three experiments carrying out in triplicate.

Fig. 4: soluble T GF-RII suppresses the effect of 1 inductive NSC of TGF-β inhibition of proliferation

The rodent NSC culture of growing up exists or does not exist under the solubility anti-TGF-beta RII antibody (500 nanograms/milliliter) through the recombinant human TGF-of 10 nanograms/milliliter β 1 processing 7 days.At the 7th day, in hemocytometer, get rid of calibrating and come living cell counting by trypan blue.Data are expressed as the mean number ± SD from three experiments carrying out in triplicate.

Fig. 5: can be with the cell sorting technical point from TGF-β R _II-express cell

As the rodent NSC that grows up of preparation as described in the example 1.Express the cell of TGF-bRII with the antibody purification of anti-TGF-bRII.About 20% NSC expressed receptor, and can use the described cell colony of this method enrichment.

Fig. 6: the antisense oligonucleotide of anti-TGF-beta RII in vitro suppresses the downward modulation of adult neural stem cell of 1 inductive of TGF-β and precursor cell propagation

Expression 1 inductive neural stem cell of TGF-β and the effect of precursor cell inhibition of proliferation are handled by antisense fully and specifically and are blocked.

Fig. 7: in vivo handle the blocking-up that to save cell proliferation in the adult brain of 1 inductive of TGF-β with TGF-RII specific antisense oligonucleotide

Fig. 7 proves the downward modulation of cell proliferation among 1 inductive hippocampus of TGF-β toe dentate gyrus (Fig. 7 A) and inferior ventricle district (Fig. 7 B).Can't block this effect with the processing of missense oligonucleotide, and antisense oligonucleotide is handled blocking-up TGF-β 1 effect (Fig. 7 A and B).

Fig. 8: in vivo handle the blocking-up that can stop cell proliferation in the adult brain of 1 inductive of TGF-β with TGF-RII specific antisense oligonucleotide

Fig. 8 proves that the downward modulation of cell proliferation among 1 inductive hippocampus of TGF-β toe dentate gyrus (Fig. 8 A) and inferior ventricle district (Fig. 8 B) can be stoped by carrying out pre-treatment with the processing of TGF-β RII antisense oligonucleotide.

Embodiment

Example

Example 1

TGF-β 1 suppresses the propagation of adult rodent neural stem cell and precursor cell.

(3-4 month big for kill adult female mice (various kind) or Fischer-344 rat; Charles River Germany), removes brain and spinal cord, and places and contain 4.5 grams per liter glucose (Merck, (PAN is Germany) in (DPBS/glu) for 4 ℃ of DPBS Germany).Remove and cover meninx and blood vessel.Under aseptic condition, remove hippocampus and ependyma district, comprise the following and ventricle inferior segment of epidermis from the sidewall of tricorn (SVZ).The tissue that cuts is transferred among the fresh DPBS/glu, cleans once, be transferred to petri diss (Petridish) and mechanical dissociation.Clean cell suspending liquid washing excessive blood off with DPBS/glu, and resuspending is in no Mg ₂/ Ca ₂(PAA, Germany) contain 0.01% papoid (Worthington Biochemicals among the HBSS (PAN), England), 0.1% Dispase II (dispase II) (Boehringer Mannheim, Mannheim, Germany), 0.01%DNase I (Worthington Biochemicals) and 12.4 mmoles/rise MgSO ₄PPD solution in, and at room temperature digested 30 to 40 minutes.Ground cell suspending liquid in per 10 minutes.Collection is through dissociated cell, and resuspending is in containing 2 mmoles/rise in the serum-free DMEM/F12 substratum of L-glutaminate and 0.1 grams per liter penicillin/streptomycin, and cleans three times with the fine grinding thing.At last with single-cell suspension liquid resuspending in be supplemented with B27 (Gibco BRL) (NB/B27), 2 mmoles/rise L-glutaminate (PAN), 0.1 grams per liter penicillin/streptomycin (PAN), 2 grams per milliliter heparin (Sigma, Taufkirchen, Germany), 20 nanograms/milliliter bFGF-2 (R﹠amp; DSystems is Germany) with 20 nanograms/milliliter EGF (R﹠amp; D Systems, NB substratum Germany) (Gibco BRL, Germany) in.In hemocytometer, get rid of calibrating and come living cell counting by trypan blue.Cell inoculation in the T-25 culture flask, and is contained culture in the incubator of 5%CO2 and keeps under 37 ℃.Unicellularly in suspension culture 5 to 7 days begin to form spheroid, and it is agglomerating to continue raised growth in coming weeks.Changed half substratum in per 7 days.The cell in the 3rd to 20 generation is used for testing (Wachs, F.P., people such as S.Couillard-Despres, Lab Invest2003,83 (7), 949-962).The culture of neural stem cell and precursor cell is called NSC in addition.For dissociation process, in 15 milliliters of centrifuge tubes, collect the substratum contain floating neural spheroid, and under 120 relative centrifugal forces centrifugal 5 minutes.Centrifugal fritter resuspending in 200 microlitre Accutase (Innovative Cell Technologies Inc. is by the PAA distribution), and is ground about 10 times with pipette.Subsequently cell suspending liquid was cultivated 10 minutes down at 37 ℃.Regrinding is through dissociated spheroid, and resuspending is in 800 microlitre NB/B27 substratum.Centrifugal through dissociated cell 5 minutes under 120 relative centrifugal forces, and resuspending is in the NB/B27 substratum.In hemocytometer, get rid of calibrating and count aliquots containig to determine the amount of viable cell by trypan blue.With cell (10 ⁵) coated plate is in the NB/B27 substratum of the T75 culture flask that is used for long-term subculture (every flask contains 10 milliliters of substratum).Accutase handles the cell proliferation that is obtained after the neural spheroid of one-level and produces the neural spheroid of secondary.Make the neural spheroid subculture of secondary 7 to 9 days after the neural spheroid cell of coated plate one-level.Similar to the neural spheroid of one-level culture and one-level, the unicellular propagation that is obtained after the neural spheroid of secondary dissociates and produce three grades of neural spheroids (Wachs, F.P., people such as S.Couillard-Despres, Lab Invest 2003,83 (7), 949-962).With 10 ⁴Individual NSC is inoculated in the NB/B27 substratum of 1 ml volumes in 12 orifice plates, and grows 7 days.Inoculate back 2 hours, 3 days and 6 days recombinant human transforminggrowthfactor-(TGF-β 1) (R﹠amp by the various concentration of adding (0,2.5,5,10,50 and 100 nanograms/milliliter); D Systems Germany) comes irritation cell.At the 7th day, by using the Accutase culture that dissociates, and in hemocytometer, get rid of calibrating and come living cell counting by trypan blue.TGF-β 1 in vitro suppresses the propagation (Figure 1A) of adult neural stem cell and precursor cell in the dose-dependently mode.

In the neural precursor cell of human foetus, observe similar action.In 7 days, handle about 50% (Figure 1B) that cell proliferation can be reduced to contrast with 50 nanograms/milliliter TGF-β 1.

Example 2

The effect of 1 pair of neural stem cell of TGF-β and precursor cell is a reversible

In order to determine whether the effect of 1 inductive growth-inhibiting of TGF-β is reversible action, stimulated 7 days with 1 couple of NSC of 10 nanograms/milliliter TGF-β according to example 1 described experimental program.After dissociating, in hemocytometer, get rid of calibrating and come living cell counting by trypan blue, and with 10 ⁴Individual NSC through factors stimulated growth inoculates, and cultivates under the situation that is with or without 10 nanograms/milliliter TGF-β 1 according to example 1 described experimental program.Carried out described dissociating/count/inoculate program in per 7 days.As shown in Figure 2, cultivated for 3 weeks after, compare with previous undressed cell, the multiplication rate of handling cell at the initial TGF-β 1 that does not have TGF-β 1 time growth returns to normally.The effect of this indication 1 pair of adult neural stem cell of TGF-β and precursor cell is a reversible.Can further not reduce cell proliferation with TGF-β 1 long-term cultivation.

Example 3

Anti-TGF-beta R _IIAntibody can reduce by the effect of 1 couple of adult rodent NSC of TGF-β

By use as example 1 described Accutase dissociate low algebraically without stimulating 7 ages in days nerve spheroid.Gained single-cell suspension liquid is used for blocking-up and analyzes.With in the NB/B27 substratum of 1 ml volumes in 12 orifice plates 10 ⁴The adult rodent NSC of density inoculation of individual cell.Stimulated preceding 1 hour back 2 hours of inoculation with 10 nanograms/milliliter TGF-β 1, in substratum, add various concentration in and anti-TGF-beta R _IIAntibody (R﹠amp; D Systems, Germany).Inoculation back 3 days and 6 days, by add with the 1st day carry out the identical anti-TGF-beta R of program _IIAntibody and TGF-β 1 come irritation cell again.At the 7th day, by using the Accutase culture that dissociates, and in hemocytometer, get rid of calibrating and come living cell counting by trypan blue.Interesting is to add anti-TGF-beta R _IIAntibody self can reduce the propagation of NSC.Even under used maximum concentration (10 mcg/ml), anti-TGF-beta R _IIAntibody only can partly suppress 1 inductive effect of TGF-β (Fig. 3).

Example 4

Soluble T GF-β _IISuppress 1 inductive NSC of TGF-β inhibition of proliferation fully

According to the laboratory manual (R﹠amp of manufacturer; D Systems, Germany), human TGF-β R will encode _IIThe dna sequence dna of 159 amino-acid residue cell foreign lands (people such as Lin, Cell 1992,68 (4), 775-785) are blended in the Fc district of IgG 1, and express chimeric protein in mouse myeloma cell line NSO.By use as example 1 described Accutase dissociate low algebraically without stimulating 7 ages in days nerve spheroid.Gained single-cell suspension liquid is used for blocking-up and analyzes.With in the NB/B27 substratum of 1 ml volumes in 12 orifice plates 10 ⁴The adult rodent NSC of density inoculation of individual cell.Stimulated preceding 1 hour back 2 hours of inoculation with 10 nanograms/milliliter TGF-β 1, in substratum, add the biological activity soluble recombined human class TGF-β sR of various concentration _II/ Fc mosaic (R﹠amp; D Systems, Germany).Inoculation back 3 days and 6 days, by add with the 1st day carry out program identical TGF-β sRII/Fc mosaic and TGF-β 1 and come irritation cell again.At the 7th day, by using the Accutase culture that dissociates, and in hemocytometer, get rid of calibrating and come living cell counting by trypan blue.Interesting is to add TGF-β sR _II/ Fc mosaic can be blocked 1 inductive effect of TGF-β (data not shown) fully in the dose-dependently mode.By pre-dispensing soluble recombined human class TGF-β sR _II/ Fc mosaic (soluble T GF-β R _II) remove 1 inductive growth-inhibiting of TGF-β (Fig. 4) that active TGF-β 1 in the cell culture supernatant liquid can block grow up neural stem cell and precursor cell significantly fully.

Example 5

Can be with the cell sorting technical point from TGF-β R _II-express cell.

Present method does not allow quick and believable the separation and purifying of neural stem cell and precursor cell.In order to study the possibility of separating pure neural stem cell and precursor cell colony based on the expression of definition surface markers, we by different technologies according to TGF-β R _IIExpression separate neural stem cell and precursor cell.The enough two kinds of technical points of energy are from TGF-β R _IIExpress neural stem cell and precursor cell i) FACS-sorting (data not shown), ii) MACS-sorting.Will be under the room temperature through dissociated adult neural stem cell and precursor cell and the anti-TGF-R of 10 mcg/ml _IIOne-level antibody (R﹠amp; D Systems Germany) cultivates 20 minutes together.After 1 PBS cleaning step, cell (Dianova) is cultivated with the anti-goat PE of secondary antibody rabbit (1: 500).After 1 PBS cleaning step, (Miltenyi Biotech Germany) uses coupling in three grades of antibody staining cells of the anti-PE of paramagnetic bead according to manufacturer's laboratory manual.(Miltenyi Biotech Germany) uses MACS-system magnetic force sorting cells suspension, and counts feminine gender and the positive cell after the sorting and be dissolved in (Fig. 5) in the culture according to manufacturer's laboratory manual.All of about 20% are TGF-β R through sorting cells dyeing _IIPositive.

Example 6

The antisense oligonucleotide of anti-TGF-beta RII in vitro suppresses the downward modulation of adult neural stem cell of 1 inductive of TGF-β and precursor cell propagation.

Described in example 1, prepare, dissociate and the coated plate cell.Subsequently be with or without 10 nanograms/milliliter TGF-β, 1,10 micromoles per liter TGF-β RII antisense oligonucleotides 5 '-cagcccccgacccatg-3 ' (SEQ ID NO:3), positive MODN 5 '-catgggtcgggggctg-3 ' or missense 5 '-situation of catccccggacccgtg-3 ' under 1 week of culturing cell.Oligonucleotide is modified through phosphorothionate, and changes the substratum that contains oligonucleotide every day.Attention 1 inductive nerve trunk of TGF-β and presoma inhibition of proliferation are handled by antisense (SEQ ID NO:3) fully and specifically and are blocked (Fig. 6).

Example 7

In vivo handle the blocking-up that to save cell proliferation in the adult brain of 1 inductive of TGF-β with TGF-RII specific antisense oligonucleotide.

Described example proof i) TGF-β 1 merge to the effect of in vivo neural stem cell and progenitor cell proliferation and ii) TGF β RII antisense oligonucleotide handle rescue to this effect.Therefore, the following experiment of design:

In TGF-β two weeks of 1 ventricle endomixis, then TGF-β 1 merges altogether with oligonucleotide.Carry out experimentation on animals according to European Communities on the 24th Council Directive November in 1986 (86/609/EEC).(Stadt Land) implants two months big male Fischer-344 rats (n=24) to be used for brain inner room infusion as indicated above for model 2001, Alza with being connected in the stainless steel pipe that permeates minipump.Animal receives the reorganization TGF-β (having 500 nanograms/milliliter in the pump) or mechanical brains spinal fluid (aCSF) (each n=8) two weeks in contrast of 0.5 microlitre/hour flow rate.After second week, change pump, and in ensuing two weeks, the combination of aCSF, TGF-β 1 (having 500 nanograms/milliliter in the pump) or TGF-β 1 (having 500 nanograms/milliliter in the pump) and thiophosphatephosphorothioate oligonucleotide (existence 1.64 mmoles in the pump/rise concentration) is infused in the ventricle.Oligonucleotide is described in the example 6.At the 27th day, animal received 200 mg/kg bromo-deoxyuridines (BrdU) of single peritoneal injection.Second day, perfusion 4% Paraformaldehyde 96 in the animal via heart.Handle tissue to be used for as described color development or surface fluorescence immunodetection at 40 micromoles per liter sagittal sections.With being equipped with Spot digital camera (Diagnostic Instrument Inc, Sterling Heights, USA) Leica microscope (Leica Mikroskopie und Systeme GmbH, Wetzlar, Germany) or laser confocal scanning microscope (Leica TCS-NT, Bensheim Germany) carries out the surface fluorescence analysis.One-level antibody is: and rat α-BrdU 1: 250 (Oxford Biotechnology, Oxford, UK).Secondary antibody is: conjugate to fluorescein (FITC), rhodamine X (rhodamine X, RHOX), CY5 or vitamin H 1: 500 donkey α-goat, mouse, rabbit or rat (Jackson Immuno Research, West Grove, PA, USA).In order to count using system and random process.Be arranged in minimum, middle and three 50 microns * 50 microns counting frames counting BrdU positive cells of the tangent plane of high part of SVZ at each.The positive profile that the top focusing surface (eliminating face) of counting frame or sidepiece are got rid of the border is cut apart in no count.Positive profile sum be multiply by the ratio of reference volume and sample volume, with the estimated number of the BrdU positive cell that obtains each structure.Calculate Interhemispheric all extrapolated values, and should multiply by 2 to represent total brain value.Data are expressed as mean+SD (SD).Between TGF-β 1 treatment group and control group, use not in pairs, both-end t calibrating relatively (student t calibrating) carry out statistical study (StatView Software, Cary, NC, USA).Suppose that conspicuous level is p＜0.05.Fig. 7 proves the downward modulation of cell proliferation among 1 inductive hippocampus of TGF-β toe dentate gyrus (Fig. 7 A) and inferior ventricle district (Fig. 7 B).Do not block this effect with the processing that the missense oligonucleotide carries out.On the contrary, antisense oligonucleotide is handled (SEQ ID NO:3) blocking-up TGF-β 1 effect (Fig. 7 A and B).

Example 8

In vivo handle the blocking-up that can stop cell proliferation in the adult brain of 1 inductive of TGF-β with TGF-RII specific antisense oligonucleotide.

This example proof is handled the downward modulation that can stop cell proliferation in the adult brain of 1 inductive of TGF-β to the antisense oligonucleotide of TGF-β RII.

With one week of oligonucleotide ventricle endomixis, then TGF-β 1 merges altogether with oligonucleotide.Carry out experimentation on animals according to European Communities on the 24th Council Directive November in 1986 (86/609/EEC).(Stadt Land) implants two months big male Fischer-344 rats (n=24) to be used for brain inner room infusion as indicated above for model 2001, Alza with being connected in the stainless steel pipe that permeates minipump.Animal receives thiophosphatephosphorothioate oligonucleotide (exist in the pump 1.64 mmoles/rise concentration) or aCSF in first week, and receives aCSF, TGF-β 1 (having 500 nanograms/milliliter in the pump) or the TGF-β 1 of infusion (existence 500 nanograms/milliliter in the pump) and thiophosphatephosphorothioate oligonucleotide (existence 1.64 mmoles in the pump/rise concentration) altogether in the second and the 3rd week.Oligonucleotide is described in the example 6.At the 20th day, animal received 200 mg/kg bromo-deoxyuridines (BrdU) of single peritoneal injection.Second day, perfusion 4% Paraformaldehyde 96 in the animal via heart.As processing as described in the example 7 and analyze tissue.Fig. 8 proves that the downward modulation of cell proliferation among 1 inductive hippocampus of TGF-β toe dentate gyrus (Fig. 8 A) and inferior ventricle district (Fig. 8 B) can be stoped by carrying out pre-treatment with TGF-β RII antisense oligonucleotide (SEQ ID NO:3) processing.

Example 9

The pharmaceutical formulation that comprises at least a antisense oligonucleotide

The moisture composite of Three Represents that is used for antisense oligonucleotide:

1. in aCSF: 148.0 mmoles/rise NaCl, 3.0 mmoles/rise KCl, 1.4 mmoles/rise CaCl ₂, 0.8 mmole/rise MgCl ₂, 1.5 mmoles/rise Na ₂HPO ₄, 0.2 mmole/rise NaH ₂PO ₄(pH7.4), 100 mcg/ml rat blood serum albumin, 50 mcg/ml gentamicins (Gentamycin)

2. in 0.9%NaCl

3. in H ₂Among the O.

Sequence table

＜110〉Regenion GmbH

＜120〉the TGF-R signal that is used for the treatment of the CNS illness transmits inhibitor

<130>HPT-P01374WO

<140>PCT/EP2005/001298

<141>2005-02-09

<150>EP?04002846.6

<151>2004-02-09

<160>96

<170>PatentIn?Ver.2.1

<210>1

<211>89014

<212>DNA

＜213〉homo sapiens

<400>1

CAGCCACACT?GTCTTTAACT?CTCAGCCCAC?CCACACTGAG?GAGGGTGCCT?AGAGGTTCTA 60

TTTCCAAACC?TTTGCATGTA?TCTTAAAAAT?CTCAATAAAA?TGAGACCTTC?CACCATCCAA 120

ACAGAGCTGA?TATTCTCACT?ACCAGTCCCT?CTCTAATATT?CCTATTTGGC?TGAAAATAAG 180

TAGCTTCAAA?AAGTTTTAAA?AAAGAGATTA?CTTGCAGCAT?TAACACTTCT?TTGTTGATTA 240

ACAAGTTTCC?TATGGAGTTT?TAAAGCTCAT?ACTTTGTTCT?TGTCCTTGTG?GACACAAATT 300

TTCTAACTGC?AAATGGGACC?TTTGTGTCCC?ACATTCAAAT?CCTCTCTAGT?AATTTCTGCA 360

AAGGTTGAGA?AGGCTGGCAT?GATGGAGAGA?ACGGTAACCA?TGAGGAAAGC?TTCTTGGAGT 420

AAAGCACTCC?TCTCTCCAAT?GCAGAGGGTA?AAACTATTAA?CATATAAGCA?AAAGAAACTT 480

GGGCTAACTG?AGACCCTTAA?AGGAGTTCCC?CTTTAGTCCA?ATAAAAGGCC?AACTTCAAAT 540

CTTAACACCA?GATAAGGTAG?TCAAAATCAT?ATTATATACC?CAGAGAATGA?CTGCTTGAAT 600

GGACATTTCT?TACAAGGGAC?CTTGGTTAGG?TGCAGATTTA?ATTCCTAGAC?TGGGGTCCAG 660

GTAGGCAGTG?GAAAGAGCTA?ATGTTTACAG?TGAGAAGTGA?GGCAGCTTTG?TAAGTGTCTC 720

CACACCTTCA?CATTTTGTGA?ACGTGGACTG?GAGATAACTG?AAAACCATCT?GCTATCCTTA 780

CCTGGGGATC?CAGATTTTCC?TGCAAAATCT?CCAAATATTT?ATAAAGTGGC?TTCACTTTTT 840

GAAACGCTGT?GCTGACCAAA?CAAAACATAT?GTTTAGAGTG?CCTGAGGTCA?TAGTCCTGAC 900

AATGATAGTA?TTGTGTAGTT?GAAATCCTCT?TCATCAGGCC?AAACTGTGCT?TGAGCAATCA 960

GGAGCCCAGA?AAGATGGAAC?CCATTGGTGT?TTGTATAGAA?AACTAGAAAA?TCAAGTCAAG?1020

TGTAATGAAA?AAGTAAACAC?GATAAAGCCT?AGAGTGAGAA?TTTGCTCCTT?TTTAGAAAAG?1080

GATGAAGGCT?GGGAGCAGAG?AATAGTAACA?TAAGTGCAGG?GGAAAGATGA?AAAAAAGAAC?1140

AATTTTTCAT?TAGTAGATGG?TGGGGCAATC?GCATGGATGG?GGACATCTGT?TCTGATTTTT?1200

CTGCAACCCA?TGAAGGTAAA?AAGTGGGGTT?CAAAACATTC?AAGGTATTAA?AGATGGGGTA?1260

GAGTTTCTAA?ACTAGGTTGA?GGGAGAGTTT?CTAAACTAGC?CCCCCAGATT?TGGGGCTTGG?1320

AGCTTAAATG?AAAAGTCCAG?GAGAAATAAG?GGCACACAGG?AACCCCGGGA?ACACTGGTCC?1380

TCAAACAGTG?CCACTGTACT?TAGTTCCATG?GCCAGAAGAG?AAGTGCTAGG?CAGGGAATGA?1440

TTATTTTGCA?AAAGCAAGTG?CAATGTGGTC?ATAGCTGGCT?GTGAGACATG?GAGCCTCTTT?1500

CCTCATGCAA?AGTTCACTGT?TTTACAGTCA?GAGAACCACT?GCATGTGTGA?TTGTCAAATG?1560

CTAATGCTGT?CATGGGTCCC?TTCCTTCTCT?GCTTGGTTCT?GGAGTTCTCC?AATAAAACCA?1620

ATTTCCTGGG?AATATTTGAT?GTTTTTCCTT?GTCTCTTTTC?AAGGTATGGC?TATATATATA?1680

GAGCTATAGA?CATATATAGA?TATATATATA?TATATATAAA?ACATAGCTAT?TCATATTTAT?1740

ATACAGGCAT?TAATAAAGTG?CAAATGTTAT?TGGCTATTGT?AAAAATCAAT?CTCATTTCCT?1800

GAGGAAGTGC?TAACACAGCT?TATCCTATGA?CAATGTCAAA?GGCATAGAAT?GCTCTATGTC?1860

ACCCACTCCC?TGCTGCTGTT?GTTTCTGCTT?ATCCCCACAG?CTTACAGGGA?GGGGAGTGAC?1920

CCCCTTGGTT?TTCCAGGAAG?CATCAGTTCA?GGGGCAGCTT?CCTGCTGCCT?CTGTTCTTTG?1980

GTGAGAGGGG?CAGCCTCTTT?GGACATGGCC?CAGCCTGCCC?CAGAAGAGCT?ATTTGGTAGT?2040

GTTTAGGGAG?CCGTCTTCAG?GAATCTTCTC?CTCCGAGCAG?CTCCTCCCCG?AGAGCCTGTC?2100

CAGATGCTCC?AGCTCACTGA?AGCGTTCTGC?CACACACTGG?GCTGTGAGAC?GGGCCTCTGG?2160

GTCGTGGTCC?CAGCACTCAG?TCAACGTCTC?ACACACCATC?TGGATGCCCT?GTAGCGGGAA?2220

AGAGATCCAA?AGGGCACCAT?GAGTTGGTGG?GCTCCGCGGA?AGGCAAGGTG?GCCTGCTGAC?2280

CTTGTTGCTA?TAGTGAGTGC?AAGCAGGGTC?CAAAAGTGCC?TGTGCATTTA?ACATGTGCTG?2340

ACTGAGTGCC?TGCTGCTGCA?GGCCAGCCAG?TTCCATGTGG?AAAGGGTGGT?GGGGGGTTTG?2400

TGCTGGTGGC?AGCTGTGCTC?AAAACCTACC?ATACTTTTTG?GCTCTGGTGC?TATCTGATCA?2460

CAATAGGTCC?TGACAGCACA?ATGATCCTCT?GCTGGGCTTC?TGGGGTACAC?TAACACTCCC?2520

AACACCTGAA?AATTCCCCAT?GTAGTGGCCC?TTAATATCAT?TTCAACACCT?TTCTATTTAG?2580

AGAAGTTCTC?GCTTCACAGC?AAAATTGAGT?GGAAAGTACA?GAGAGTTTTC?ACAAAACCCC?2640

TTCCCCATAA?AGGCACAGCC?TTCTCCACCT?TGACATCATG?CATGCATCTA?TGAGGTACAT?2700

TTGTTATAAC?TGATGAACTA?ACACTGACGT?ATCATTATCA?ATCAAATTCA?TAGTTTACAT?2760

TAGGGTTCAC?TCTTGGTGTT?GTATATTCCA?GGGGTTTTGA?CAAATGTATA?ATGACATGTA?2820

TCTACCATTA?TAGTATCATG?CGGAATAGTT?TCTCTGCCCC?TCAAATTCCC?TGCATTCCAC?2880

TTATTCATCC?CTCCCTCCAT?TCCCCTAAAT?TTCTGGCAGC?CACTGATTTT?GTACTGTCTC?2940

TGTAGTTTTT?GCCTTTTCCA?GAGTGTCATA?TAGTTGGGTC?ATATACACTG?TTCTATTTTA?3000

ACAGGGCTGA?TTACCCCCGT?CAGAATTGTA?TGCAGGCATT?AGCATGGTTT?CATTTTCTAT?3060

AGGCCACACA?TTTTGTAGAG?TGATTCAGTA?GCAGCTTCTA?CGAGCTGCCA?AGGATGACCT?3120

CTGGGATGCT?CCATTCCTCT?CCAACAACAT?TGGGTTGAAC?CCTGTGAAAC?AGCTGCCTAT?3180

GTGGGTCAGG?CATGCTTAAC?TCTATGCCAT?TTCCTAGGGT?TCACCCTAAC?CGAATCAAGC?3240

TCCCATCCAA?GGAGACCATC?CAGGAGATCC?TGCCCAGGAA?GGTGGCAAGA?GTTTTCTCTC?3300

ACTGGCTTAA?TTTTTATTTT?GCATTGCAAA?TATTTTTGTT?ATCATTTCAA?ATCCTTTTTG?3360

GAAATAAAGC?AGGCAGGAGT?TAAGTAAATG?GTCTGATAGG?TGGAAATAGA?GTGTGCTCCT?3420

CCCAATTGTA?AGATCAACAT?TGCTAATGGG?ATCCCTCACA?CAGGTGGCTG?GGAGTGGGAT?3480

GGATAAATCT?CAAAACTACC?TGGGAGAGCT?GGCACTTTTT?CTACTTGTTT?TCTAATACCA?3540

ACAACTTTCC?AAACACACCT?AGGAGCCTAT?CTCTCCCTCC?CCACCCGATG?AGTTCATGAT?3600

GTTAAATTAA?TTGCATAATT?CACCTAATTG?ACAGTATTGA?CAGATGGCCC?TGTTAAGAGT?3660

AGAGTGCTAT?TGTTGGTACA?CAAGTAACAT?TTATTTTATT?CTGGCACTGT?AATTACAGGC?3720

AGTAAATTAA?ATTAAATATT?AAGCATTAAC?TTGAAATCAA?TAGGGCAACA?AATCTCATTA?3780

TGAGAAAAAA?TGTATTATGC?AAATTCTTTT?CAGAATTTTA?TCATCATGAA?TAATGGCTTC?3840

ATTACGAGAA?CTATACAGCA?GAGGAGGCAA?CAGAGTTTGA?AAGAAACATA?ACACTCCAGC?3900

ACATTCTGAT?TTCAGAATTT?ATGCAAAATA?TTCTTACAGT?TTTAGTGTCA?AAGAGGATTT?3960

GCTCAAAACT?CCAGAGAAGC?CTGTGACCCA?CCACAGCCTG?GTTCCCCCTC?GCCAACCTCC?4020

TCGGACTTTA?TTAAGGTCTG?TCTGCTGAAG?TGGCTCTGGG?CCAGGACTGG?CACAGACCAG?4080

ACTTCCTGCT?CCATTTGTCT?TCCCGATTGT?GCCTGATTTG?TTGTTTCTGT?TTCTTATCTG?4140

AATTTGCCTT?GCCCTTAGGG?AAACCAACAA?CTTAGCCTCG?GCCTTCATGG?TTGAGGGAAT?4200

TCATCCAAAA?GAGGCAATAA?AAGGTTTTAG?TCAGTAGAAA?GAACAGTCTT?CTCAGTGAGA?4260

TAGGGCCACA?CTGTTCTCTC?TCATTCTTCA?CTAAGGGCTC?CTTCCTGGGT?GTGTCAGACA?4320

TATAGCTGGT?TCTGACTCAC?TCACAACCTA?TCGTTTTCTT?TTTTCTCTGA?CCATTGCCCT?4380

CATCAAAGTG?CCCCCAAACA?AACAATTTGG?ATCAGCCTCT?TTATGAGTCC?AGAATGACTG?4440

CCCTGCTATG?GACAGCCTTA?GCTAGCATTT?CTTAACAAGG?AAAAATAAGA?GGCCATTAGG?4500

ATGTTCCCAA?CAGACAGATT?TCTCGTTCCT?TCCAGGGCAT?TCTCCTCTTC?TTTGCTTTCC?4560

TTAATTCCAG?AGTGAGGAGT?CGGTCTCCTC?TTTCCCACGC?GTGCTCACTC?AGGCCTCTCC?4620

CAAGTCTGTG?AGCACAGCCT?GCAAACACCT?GTACACAGCC?TTCTGCATGC?CACAGTCACT?4680

TCTCACTACA?GCTGCCTGAC?AAACCCTGCT?TGTTTTGCAT?CTGCTAAGTA?TTTCCTTATG?4740

GAGCTGAAGA?TTCCCAGAAG?AAAACATTTG?GAATCCAGAG?GGAATCAAAT?ATAAACTCCT?4800

GACGTGAAGG?CCCAGGAGTA?AGTAGCAGAG?GCTGCAAACA?AAATGTTTTA?ACCCAGGACC?4860

AAGGGGGCTT?GGAAAATGTG?GCAAATGTCC?TCCGAATGGC?TATTTGTGAA?CTCTCAGAGT?4920

ACATATCAGC?TGGTTGGAGC?CTATAATAAT?TGGGTTATCC?ACTGTATTGA?AATTTGCTTT?4980

ATAAACAAAA?TTTAACAGGG?CCATAGAACA?CAATGGGACC?TTCCCTCAGA?TTTAAGCTCA?5040

ATATTCCAGA?ATTCTCTGCC?ACCTAAGAGG?CAACTTGGTT?GAATCTTACT?GACCTTTGTA?5100

AACACTCACT?CCTTACCTGG?TGGTTGAGCC?AGAAGCTGGG?AATTTCTGGT?CGCCCTCGAT?5160

CTCTCAACAC?GTTGTCCTTC?ATGCTTTCGA?CACAGGGGTG?CTCCCGCACC?TTGGAACCAA?5220

ATGGAGGCTC?ATAATCTTTT?ACTTCTGTGA?AGAAAGCCAG?CAAACACAGG?GTCACTGAGA?5280

ATGGCATGTG?CAGCCAAAGG?AAATGAGCAT?GGTGAGATGC?CTGGCTGGGG?AGCATGAAGC?5340

ACTAAGTAAC?AAATACATAC?GTAATTACTC?TAAGAGCAAA?TTTTAATAAT?AATGGCTAAG?5400

ATAAGAAGGA?AGGAGTGGTT?GGGGAAGGGC?TAGAGAAGTA?TTCAATAAAT?GATTGTTGAG?5460

TACTTAAAAT?GTGCTAGGTG?TTATGCTGGG?GGACACAGTG?GACAACAAGA?TAGAGAGGGT?5520

CACGGAGCTT?AGGTTTTAAC?ACAGGCATTT?TCTACAGGGG?GATATTGCAG?CAAAAGGGTG?5580

AAACTGGTTC?TTGGGAAGTG?GAAAAATCTT?ATGTATTACA?ATGGTTTGTG?AGCCTCCAAA?5640

GGCCCAGAGT?ATACAAAGAG?ATTTAAAATG?TGGTATTAAA?TTTCATGTAG?GTATTGAGGC?5700

ATAAAAAGGA?ATGAAACTCT?GGCACATGCT?ACAACATGGA?TGAATCTTGA?AGACATTATG?5760

CTAAGTGAAA?TAAGCCAGAC?ACAAAAGGAC?AAATATTGTA?TCATTCCACT?TGTATGAAGT?5820

ACCTTGTACA?GGTATATTCA?GAGACAGTAT?AATGGTGGTT?GTCCAGGGGG?CAACCTGGGA?5880

GGAAAGGGTA?GGAAAAGTTA?TCCTTTAAGG?GGTAAAGAAT?TTCAGTTGAG?CAAATTTCAG?5940

TACAGAAAAA?TGAATAATGG?TGATGGTTGT?AGAGCACTGC?GAAGGTACTT?AATGCCAGTA?6000

AACTGTACAC?TTAAAAATGG?TTAAGATGGT?ACATTTTATA?TTATGCCTAT?TTTGCTACAG?6060

AAAAACATCA?TGGAGAGTAG?TGTTTAGAAA?AAAAGTTGTC?TACAGGCCAG?GTGCTGTGGC?6120

TCATGTGTGT?AATCCCAGCA?CTTTAGGAGG?CTGAAGGAGG?ATATCTTGAC?TCCGGGAGTT?6180

TGAGACCAAC?CTGGGCAACA?TAGCGAGATC?CTCTATCTAT?ACAAAATAAA?AAACAAAACA?6240

AGCAAACAAA?AAAAGTTGTT?TAAAAAGGCT?CCTTACGATA?TCACTGATTT?TAAAAAAGGT?6300

TGAGAAATGC?TGTTTTAGTG?GGAAGACAGA?GGGGACAGAT?TAACAACATC?AACAAAATTT?6360

TAAAACGATA?ATTTTCCTCT?GATGGTATAT?TCAATAAAGA?AAATGATAAA?GGAGGAGGTA?6420

ACCCTTCACC?GGGGCCTCAG?GCTTCAACTA?AGGTCAAATT?CTTTATAAAA?ACTTCCTTGA?6480

ACATCCTTAG?GGTCAATCTT?GGTTAGATAT?CCTGGGCAGG?GCTCTATTCG?TGCATATACC?6540

ATATTTTATT?TAATATATTC?ACCTGCTTAT?TTTTCTCACC?TAACTGGACT?GTGAGCATTT?6600

GGGTGCAAGT?TGAGTCCCTT?TCTCATTCTT?GTATTCTTGG?TGCCAATTGC?AAGGGTCTCC?6660

CATGCCAACA?GGCTGTCAAC?AAATGCTTTG?TTGAGTGAGT?GAATGAATGA?ATGAATGAAT?6720

GAATCTTAGA?TTCTCTCCAA?AGTGGCAGTG?CATAAACTCT?GGCCAAACAT?TAAAACAAAA?6780

CACCAATTTA?AATGAGCAGA?TTAATATAGT?GTAAACAGAG?CACAGGACAC?TTAAAAAGAT?6840

AGAAAACATC?CCAGTACTAA?AACATGCCTG?GGCTGAAAGG?AGAGATTGGG?CTGGATTCAA?6900

CACTGTTCTC?CAAAGTAAGT?AGGATCTTTG?GCCTTTAGCT?TCAAAATAAT?CTTATTTAAT?6960

GAGTAAAACT?TTCAATACAT?TTGCACTTCT?AGGTAACGAA?TTGAAGAAGC?TTTCATGGCA?7020

AGATGACATT?TTGAAAAGGG?ACGGCTTGTT?TTTGTTCTTT?GTTCATTTGC?TTTTTTCCCC?7080

TTTTCCAGAA?CTCTACTTGA?ATATTTATCT?TTTTCAGCTT?CACCAAATAG?TAGAGCTGCC?7140

AGGATATTTT?CTTTTTTATA?GTTTTAAATA?CAGGGGAATT?TGGGATGAAG?GCCTCCCATC?7200

ACATTAAGAC?AAACCACAAA?CTATCCTCCT?GTGTGTCATG?CTTTTTGCCT?CAAAGGACCC?7260

AAGCATTTAA?TCCACATTGC?TCTTGGGTGA?GATCTGAATT?GTGATTTGCA?TAGCATTTAT?7320

ACTCTTATTT?TTTTCTTTCA?TTCCTTATCT?TCAACCAGAC?TGTAAATGCC?TAAGGCACAA?7380

GGCAGTGGCT?GAATTTGGTG?TCTTTCACTT?ATCTGCTCAG?TGCCTAAAAT?CGTGCCTTAT?7440

ACGTAGTAAG?AATTTAATAA?ATATGAGTTC?GGTTGAATTC?AAGCAAAAGA?GAAAACTGAG?7500

AATCAGATCT?GGTTCCCAGT?AAGTGTTTAC?TCTCATGTAC?TTCTTCTCTT?CTATAAAATG?7560

AATATACTGA?ACTGAGCTAC?CTCCATGTTC?CTCTTCAGAT?TTATCTTGTA?ATCCAATCTA?7620

ATCAAATATG?ATGCCCCCTT?GGTACCATAC?CTTGAGATAT?ATGTACTACC?ATATAATAGT?7680

AAAGGATAGG?ATTTGTATAT?GATATAAATT?GTTCCTTAGA?TAAGGTACAG?TCCACAGACC?7740

TTCCATCTTC?AATTGTTTTG?GCTTATGTAG?CAGCTGCAGT?TGGTGCCTGC?CAAGGTCCCC?7800

TTGACCAAGC?TAGGGCCAGC?AGCCTACAGC?TGCCACAGGT?GTTGGCTCAT?AAGGGCTCAC?7860

ACCTTCACCC?TTTTCTGGGG?GATTGTCCTT?GGCCAATGGG?AGTTGCCTAT?CCTAGAGATT?7920

CGTGGACATG?ACCGCCTTAC?TCTCAGAGGC?AGCGTATAGC?CGATGACAAA?TTAATGTTGA?7980

AGTTTAACAG?TCCAATTCTC?TTGGCTCTTG?GTGGGTAACT?ATGGTGCAAT?TCACACTCTC?8040

CAGAGCTTCC?AGTGAGATCA?AGCTGAGGTT?AGACCTCTCT?TGAAATACAA?GTTCACTTAA?8100

CTCCTTCCAT?GCCTCTTCCT?GCTTCTCTTA?CTTCCTTCTC?ATGAGAGCTT?ATCCTCAATA?8160

AATCATTGCA?CAAAAGTGTG?TCAGACTCCA?CTTCTAGTAA?AGCTGGCCCA?ACACAGCCGC?8220

CAAGGAAGTG?CTTTCTCCTC?TCTCCCTAGG?CCTTTGTCTC?AGTGAATCTG?CACAATCTGA?8280

CTGTAGCTGC?AAAGCTACCC?TGGGGAAGCC?TTGATGTAGC?CCCTTCTTGT?GAAGGTGAAA?8340

TTACTAAACC?AGGAAGAACA?TTCTGAATCT?CACATTGTAT?TACCGTTACT?CTGATGAAAC?8400

TCCTTTACCT?TTCTAGAAAG?CTTTCATGCT?TTTTCCTTTC?TACCAAGCAT?TTCAGAGAGT?8460

TCTTTCTCCT?CTGACTATCA?ACAACAATCC?CTATACTCAT?GGTCAGAAGT?GACAGAGGAG?8520

GACATGACCA?ACATCAGAGG?AGGAAAATGT?TGGGATCAGA?ATAAACCCCA?GCTGTCAATC?8580

TCATGGCTGA?TAGTCCTTGA?GAACAAAGAC?AAAGTCTTTG?TCCTTGAGAC?TATAAACGCA?8640

GACCCAATTC?ATTCCAAGTC?CTAATCTTCC?TAGTTACAAA?CACTACACAA?TTTATTGTAA?8700

TTTTTTTTAT?AGGTACTCTG?TGGATCAAAG?CAAGTTTCCA?TGGGGAATGA?GAGAAGATGG?8760

CATTGGGCAT?ATTTTTACTT?AAAGAAAAAT?TAATGAATGC?TATTTTAGAA?AGGAAGACAA?8820

AGGCAATAAT?CCCTTCCCAA?AACAAACAGA?CTTATAAATA?GGTTACTTCC?TACTTTTCCT?8880

AAAATCTTGG?AAAGTTGTGA?GACTCCCTAA?TATTCCCAAG?GGATACAAGG?CCTGCTTCCC?8940

ATCTTCGACT?TATGGGTAAT?TTCACAAGGA?AGGGAGGTCA?CGGGTAGTCT?GAAAGGTGCT?9000

GGCAAAAGGA?CTGGCTCCTT?GTGCCCCACT?GGGAGAATTT?ATGACTCTTC?TGCCTCCTCC?9060

TAAGCTTAAA?ATAGACAAGT?CTGGGGAGGG?AGGATCATCA?TTTGACCTAA?ACTGTCATAC?9120

TCTAATCCTT?TAATATTAGT?TTTTCAGATT?AGGAGTACGG?ATGGGGATCT?GCAGTGTGTG 9180

CATGATTTAG?GCTGACCTTT?CTTTAACTTC?TGAAAAATGT?CCTATTTATG?TAACATAGAT 9240

TTTCCAAAAC?AGCTAAATGC?ATGTTTGCTT?TTTTCTTTCT?AATTATGGAT?TTTTGCAATT 9300

CTTCTTTCTT?TACCCTTCTC?TCTCATTTTG?GACATCCTAC?TCCCAACCTC?CATTTTTTTT 9360

TTTCTCATGC?CCTGCAATGT?GTAGGAAGAT?GGTTTAATGT?TTGGCAGTGT?GTATACATGT 9420

GCCTCTCAGT?TAACATCTTT?GATATTCAAT?TGCAGCGATC?AGGCAACATT?GCTCATTTTT 9480

CCTACTATGG?CCATTAAGGC?AATGCCATTC?TCAGGGCCTC?CATTAGGACT?TGTAGGATGA 9540

CCATGTAACA?TGGAGGCCAG?TCCCTCCTGG?AGGGCATTTC?TTAATTGCTC?CTCAGTTCTA 9600

AGTGTCCCTC?AGAATGCCTC?AGATATTTGC?TTTGACTCAG?CAGAAGAAGG?GAAGATCGTG 9660

GCCAGAGATA?GCCTGAACCC?TGCGAGAGGA?GGTTAGAAAG?CAGAAAGCCC?TCTGCCAGCC 9720

AGGTGGGTAC?CAATGGTCGT?TCCTAGGATG?AGACCTCATG?TAACAGAGCC?CAGGCAGTCC 9780

TGGGGAACTG?GACAGAGCTG?GTGATTGGCA?ACAAGTTGAT?GGCCTGAGAC?CTTTGACACT 9840

CCCAACTTTT?TCCCCAGGGT?TTCAGGCAGC?TGGAGACTGG?GATGTTTAAT?CCACTTTGGC 9900

AAAATCTTTG?GGTCCAAACT?GTGTATCTTA?TTTATTTTTC?ATGATGGTGC?TTAAAATATT 9960

TTTATTTTGG?AAAATGCATG?TGATTAAAAC?TATGAAATGA?CTAAACAAAT?ATGTATAAAG?10020

AAATGTAAAT?CTCTCCCCAA?CTCCTAACCA?CTGTTTCTTT?CACAAAAGTG?GCTTAGGTGG?10080

AATAGTGAGA?TTAAAAGTGA?TTAAAATTTT?TCCCTTATTA?CTTGCAAATG?AGCACTTCTC?10140

AATCAATTTT?TTATAAAAGC?CCAGATGTTT?TGCCCTCAAT?TCATTGGGAA?TAAAGGCTTT?10200

GGTAAAATAC?AGTAGAAATG?AATTACAAGA?AAAATGAATC?CCACTTGAGT?GTTGTGGCAA?10260

CATCAAACTG?CTATTAAAGG?CACAAAACAC?ATCTTGGTTT?CTGTCCTTAT?ATTGCAAATC?10320

TGTAACAGAG?AGTTTGAGGA?CCAGCACCTG?CCAAAGACCA?CACTTGGAGC?AACATTGCCC?10380

TAAATGCTTC?TTAAGGAATG?TGAGATGCAT?TTTGACACAG?GAAAAAAGAG?CACAAGTTAT?10440

TAAACATATT?TTAAGGGTTT?CAAATGAGTC?AGACAAAGAA?TATTGAAAAG?GTCTTCAGAG?10500

ACGGGATCCA?ACATCCTCAT?TTTACAGTTG?AGAAAACTGA?GGCCCAAATA?GTACACTGGA?10560

TTCCAGGAAG?AGCATTTAGA?ATTGTGCACT?TTATTACTGT?TACTCTGAAG?AAATTTGCCT?10620

TTGCCTTTTT?AGGAAGCTTT?CATGCTTGCT?CATCTCTGCC?AAGCATTGCA?GAGATTTCTC?10680

CCCTAACCAG?AGCAAGTACA?GCTGGGGCAG?TCCCTGGTAT?GAACATGCCC?TTCCCAAATG?10740

TGACAAGTGT?GTCCCTCCCT?GCCTTGATGG?GGCCCTCCTC?AGCATACAAC?CTTGAGAAGG?10800

GGAACCTTAT?GGGATCTGCT?GGGTGGTTGT?TATTTGTAAT?TTCTAAGCCA?GCTATGCAAA?10860

AAAACAATTA?CAAAGAGCAG?CCCTCTCCTT?AGCTGGTATT?ATTTACCCAC?ATTAAACCCA?10920

AACACTTGTC?CTTTCTGGGT?TTAGGGAAGT?AGATGTGACT?GGTGGTGGAG?GTGAGGTAAG?10980

GATGAGAATC?TCATTTTAGC?TACAGGCATC?AGATTGGGGC?ATAGTTGGCA?ATAGAATTAA?11040

TGCAGTTCCT?CTTTGCACAT?TTGATCAAAT?GATGCTTGAC?CTTGGGCCTC?TCTCTTGTGA?11100

AGAACTGCAT?AAAAAGCAAG?TTCAGGAGTG?TGTGGGCTGA?GTCCAGAGAA?AATGTTACAC?11160

CTGGCTAACC?TATAACAAGA?ACCACCTTTT?TAAAAAAAAT?TGGAATTGCC?TCTAAGAGAA?11220

AAAGCGAAGG?CTTAGAGAGT?ATGACTGAGT?TTAGCACTTC?AAAAGTGGAA?GAGCTAACAA?11280

TATGCATTGT?AAGTATTATT?TGTTGTTTTT?GCCCTGACTC?CTTTAAAAAG?TAGATATGAG?11340

GACTTAGAAA?AGAGATGCCA?AGAGTTTGTG?CCTCACTTCC?TATATCCACA?AAATAAGAAT?11400

AGTCACATAT?GCCCCCTACA?ATTATTCAGT?GTGATGCTGC?AGGGCCAGCT?GCACCGCCAC?11460

CTCCCAACCC?CATTGCACTG?GCTCTTCCGG?TTAGGCTGGC?CCAACTCCAG?GAGGAACAGG?11520

CAGAAGGGCT?GGAGTGAACC?CTCCCAGCTC?GGCCTGGAGC?AGCCCTCCAG?CAAACTGATG?11580

GGAATTGGAA?AGATAAAACA?CCCAGCTTCC?TTTGAGTCAG?GTGGTATGAC?ACTGAGGTGT?11640

GTGTTCTGCT?CGTAGTTATA?CTCCAGTTGC?CCATGGTGGT?AACCCACTTG?ATAAGATATC?11700

CTTTACTGGT?TTCCTTCCCT?TTCCTGACTC?ATTTCCTCAT?TCTCTTACTG?GCATTTCCTG?11760

CAATCTCTTC?CCAAATAAAC?TACTAGTACT?CAAATTCTTG?TTCCAGGGTT?GGAGGCACTC?11820

CACCCAAGAC?ATATGCCTAC?ACAGCAGAAT?TAGTTCATCA?AACCAAGTCT?TTGTCTCACC?11880

CTCAGACTGT?TTCTGAAGCC?AGACAGACGG?GGCTGAACAC?CTCAGAATTT?CCCTGAGTGC?11940

CTCAAACGGC?ATCTTTTCTA?AAAAACCTCT?TTATTTCACT?GCTTGAGAAC?GACTTTCTCT?12000

TACTTCCATC?TCCCTCCCGC?CACCTCTCTC?TGCAGTCTTT?TCACTGATGG?AAGCCACCCG?12060

CAACCGCCCG?GCCCTCGCAG?CTTCTTTTAA?TTTGTCTCAA?AAGGCTCTTA?AGAGAAAACT?12120

ACGCTTGCCT?GTCTCTTCCC?AGTTCCACAA?CCCTCAGAGG?GCAGGTCTCT?GGGACAGCAA?12180

TGGTATTCCT?CGGAAAGTCA?GCATCTGGTG?CACAGCTGCT?GTTTTGACTG?TAGTCCCAAT?12240

GTAACAGGGC?AGCAAAGTTG?TTGATGGTTT?TCCCCAAAGC?AGTACCCCCG?AGTTTTCATA?12300

TCTGCTTTCC?AGACTGTGCT?CCCTTGAAAT?CCAGGAAAAT?GAAGCGTTTC?AATCCTGGTC?12360

TCTCCTCAGC?CGTCTCTCCA?ACGCCTCCTT?TTTTTCTGTC?TCTTTCTTCC?CCCAGCCCCT?12420

TCCCTTTCTT?TTTGGTTCAT?TTGCACTTTT?TTTTTTTTTT?TTTTTTTCAT?CTCACAAGGC?12480

TGCAGCAACT?TGACAATACA?CTAAGGAGCC?CTTCTTGGAG?TTGTGTTGCT?CCTCATTAAA?12540

TACTTGTTCA?GCTGGCTGCT?ACGTGTCAGC?TTCTATTCAA?AGGCCTAAAT?GCTAGGGATG?12600

TGGAAGTCAG?TGTGCTTGCA?GGCCAGTTTG?GCTGGGGATG?ACGAGAGTAT?TTTGCCTGCT?12660

GTGTTCACCA?AAGGGGGCCC?TGAACAGGAC?CGCCTTCACC?CGCCTTCACC?CGCCTTCCAC?12720

ACAACACACA?AACACTTGTA?TGAACACCAA?ACAGACTGAA?AGCCTGGGAC?AGAGATTTCT?12780

TTGTAAAAGA?GAAGCCATCT?CCAGTTCTGT?CCTTGCTGAA?TGGCGATTTC?ATGAAGCTTT?12840

TTCTCCTTTT?TCGTAGAACA?GTAACACACC?AATCACCTCC?TCTTGTCTTG?TTCTTACTTC?12900

AAACAATTCT?GAAAGATTTG?TTTTCTTTTT?TTTTTCTTTT?GTATTCTTTC?AGAGGATTAA?12960

AATGTCTGAA?ATGACAGCCT?CTTTCATTAT?CTATCCCCCA?AGTCTATTTT?TCTTTCTAAA?13020

ATCATCCCAC?CCACCCCACC?CAACTCCAAC?ATTATATTAC?ATAATCTCTT?TGTTCATTAC?13080

CTGTCCCTAA?AATACTGGCT?CTTCACTAGA?CTTCCTGTCT?CTCAAAGAAA?GACACTGCTT?13140

TTTAAACTGC?TGTATCCCTG?GCATTTTAAA?CAATGCCTGC?GACACAATAG?GTACTCAATA?13200

AATACTTTTT?GAGTGAATGA?ATGAATAAAT?ATATCTTTAG?GGAAATAAAG?ATAAAACAGT?13260

TATCTCAAAT?TTTAAGGTAT?CAATACTGTG?ACCTGCTACA?CAAATTAACA?GCCTTGGATT?13320

CTGTTAACAG?GGATTCACCC?AGAGAAGTGA?GGCCATCACT?GAATGTTCCT?CAAACATGTG?13380

ATTGTCTCCT?CAGCTTCTGC?TGGAAGGCTT?CATATCTACT?GCCAGGATGC?ACAGAGTAGC?13440

TCTGACTATC?GTATCCATAC?TGATCATAGG?AATCATAGCT?ACTATTTTTT?TTGGGGGGCG?13500

GGGGGGATGG?AGTCTCGCTC?TGTCGCCCAG?GCTAGAGTGC?AGTGGCACGA?TCTCAGCTCA?13560

CTGCAACCTC?CGCCTCCCGG?GTTCAAGCAA?TTCTCTGCCT?CAGCCTCTTG?AGTAGCTGCG?13620

ATTACAGGCA?CCCGCCACCA?TGCCTGGCTA?ATATTTTAAT?TTTTAGTAGA?GATGGCATTT?13680

CACCATCTTG?GCCAGGCTGG?TCTTAAACTC?CTGACCTCAT?GATCTGCCTT?CCTCAGCATC?13740

CCAAAGTGCT?GGGATTACAG?GCGTGAGCCT?GTACCTGTAC?ATGGCCATAG?CTACTATTTT?13800

AAATACGTTC?TCCATTGGCC?AGGCTAGCAG?TATACCAGGA?ATACTAAGGC?CTGTGAGCTA?13860

CAGAGTCAGA?CAACAGGGCT?TTGATTCCTG?GCTCCACAAC?TTTCGCACTT?CCTGAGCCTT?13920

CAGTTCTCTT?ATTGTAAAAT?GGGATTAATA?ACAGTACAGG?CCTCAAAGAG?TTTTGGTAGA?13980

TTAAATGAGT?TGATGTGTGG?AGCAAGTGCT?TAAGAAGTGG?TAATTATTCC?TTTATGGCTT?14040

TCTTTATCTG?GACCAAATGT?ACTTTCAATA?AGAAGCCTTT?CTCTCTGACC?ACTCTCTTCA?14100

CCTAACTGCA?ACACATCTGC?CGAGGCCCCT?GGTGGAATTT?TGTGCGAAAT?GAAGCTGTAC?14160

CACCTGGCTT?TTGAAGAGCT?CTATTATCAT?CTGTTTATGT?TTTCTCACCT?GATAAAAGTG?14220

AGGCTTCTCC?AGTGTAGTGC?TGTTCTTTCT?CTGTTTTCCC?TGTGCTCCCC?TGCATTCAGG?14280

GGAGACTGGC?TAGTAAAGAA?GTAACTCAGA?AGGATGCCCC?AGAGTCTTCC?TCTTCCTTTA?14340

AGAGCTGACC?TAAGTCTCAT?TCCCTGACCA?TAACACTGCA?CTCCCTGTAG?CCAACCTGGG?14400

CATTCAGTCC?TTTGAGCTCA?CTGCCTTCCC?TTCCTAAGCA?TTTATCACAA?CTGAACCACA?14460

CTTGCCTGTT?AAAAACAGAC?TAGTTAAGTG?TTCCAGTGCC?AGTAAATAGC?ATGAGACAAA?14520

GCCTGGAGGT?AAGACCTAAA?AGACATCCAT?CATGATGAAG?TGATGAACAC?AGAATGAGAA?14580

TGTGGCGTGG?AGGTGAGCTT?GGAGCCTTAA?TATCCATGTT?TATGAGTCAC?TTAAAGGCAG?14640

GCTAGGTGGG?ACTTCACAGT?TTTCTGTGAA?ATCTTCTGTC?CCTAATCCTT?GTATCCTACT?14700

TCATTCAGTT?AGACCTTCTG?CTGCTTAGAA?CATTTTTCTT?CAAGTAGTGA?GTACTGTAAT?14760

GTTAACATCC?AAGAAAGTAA?AACAAATAGT?CACCTCTGCA?ATAGCTCATT?AACAACTGGG?14820

AACAGAGAGG?TTAATGTTCC?ATAGCTTAAA?AAAGTATCAA?TACAACTAGG?GACTCTCTCA?14880

GTACAGGATG?GGGTGCTATA?TCCATATTAC?CAATGGCAGT?CATCCCGAGA?AATCCAAGCA?14940

GCCACACTTA?CTCTCCTTCA?GTGGGTAGAT?CCACTATACT?TGTCATGTAG?ATTAGCTGTT?15000

TTCACTGGAG?ACTTGCATCC?CATCATCCTT?CTGCACACAG?TTGAGGTGGA?CCATACCTCT?15060

TTTTTTTTTT?TTTTTTTTTT?TAGACGCAGT?CTTGCTCTGT?CGCCCAGGCT?GGAGAACAGT?15120

GGCATGATCT?TGGCTCACTG?CAAGCTCTGC?CTCCCGGGTT?CACACCATTC?TCTGGCCTCA?15180

GCCTCCTGAG?TAGCTGGGAC?TACAGGCGCC?TGCTGCCACG?CCCGGCTAAT?TTTTTTGTAT?15240

TTTTAGTAGA?GACGGGGTTT?CACCATGTTA?GCCAGGATGG?TCTCGATCTC?CTGACCTCAT?15300

GATCCACCCG?CCTCGGCTTC?CCAAAGTGTT?GGGATTACAG?GCGTGAGCCA?CCGCGCCCGG?15360

CAGGACCATA?CCTCTTGAGC?AGGCTTCTCT?GCAGGTGCTT?GGTAGCTGGC?TCGATGGGTC?15420

AGATCATAAG?CCTTTCATGT?CACAGAAGTG?GCCCTGATCC?ATGATCCCAC?AAGCACACAG?15480

ACTCAGAGCC?TACAGAGAAG?ATGACTCTGG?AGATCTGGTT?CCCTTTACTG?TCCATCTATG?15540

ATTCATCATA?CAAAGGTAAG?CACATTCCAC?ATTTCCTTTT?TTGAAATAAG?ACTGCTGATT?15600

TTAAAAAAAT?GGTAATTACA?TCTGCTATAC?TGCAAACTGC?AGAAGTTCAA?GCTTAAGGAA?15660

AGACCTTTTA?CATCCTTCCC?TCTTCCTTAT?ACCTTAAAAT?TAAAGTCTAA?CATCAAACAG?15720

GGGGATTCAT?TATTTAATTT?GTAAGATAAG?AAACATATCT?GCATGTGTAA?GTTTTTTAAA?15780

AAGAAGGGAG?AGGAAACAAA?CAACTGTTTC?CTGTAGACTA?CAAGCTTCTT?GAGGTCAAAA?15840

CCTGTCCTTC?CATCTGTGTT?TCTACAAAAG?CTACAGCAGG?GACAACATCA?AGATGAATGC?15900

AGTTGGAGGG?AATCCATCTG?TCTTCAGGCT?TCGTGTACTT?TCCAAAGGAC?CTTTTGAATG?15960

TAAAAGAAAA?GCCTCTGAAA?CTAAGACTAG?GCTGAAAATC?TGTCTTTAAG?GTTTTTGAGA?16020

CATGCCAAAA?AGAAACAAAC?AAAAACCACT?AATGCTTTTA?AAAGAAGAAG?TCAAGGTGGG?16080

AGAAGGAGCT?TACTACGTGA?GTTCACACGC?TTAATCAAGT?GAACGGCTTT?GTGTCAGGAC?16140

GAACGTGAGG?ATGGATAAAT?AACCTTGGTG?TCTGCAGCCC?GAGCAAAGAT?GGGAGAAATA?16200

GGACTGTGGG?CTTAAGATCA?AACGAAATGA?GAACTGGGAT?GGCCTCTTTC?CGGTTCCCCA?16260

GGGCTGTCTC?TTCTTATCCT?AAGGTTATAA?AAGGTTTTTT?GAGACTAGCT?GAATAAACCA?16320

TATCCTGTTC?CTTCCTTGGG?AAAACTTGTT?TATATTCTAA?CTGTTTTTAG?ACCTTGTAAA?16380

ATTTGGTGAA?CTCCTTCCTC?ATTAGCTTAA?ATTCTTCCAC?ACTCAGCAAA?TATCAACAGG?16440

CAAGGGTTTT?AGTCAGTGAT?AACAATGAAA?GCTGGGAGCT?CACCTAGGGC?CTTAATAAGC?16500

TGGCTGCACT?GACAGAGGGA?AAGACAGAGA?CACAATCTCC?AGCTCATGTT?TATAGAATAA?16560

CAGAGTTGAA?AGGATAGGGA?ATGATACTGA?AATCTAGGTA?AATTTATTCT?GACAGTGACA?16620

ACAGCATTGT?CTCTGATACA?ACTCATACCC?GGCTAAAGAT?TCATTTTGGA?ACTGTCAAAG?16680

CTTTCAAGCA?TAAAATTATT?CTCAGTGGCT?GAAACTTGGT?TAAACAAATT?TCACTGTGCA?16740

AGGAAAAACA?AAGTTAACTT?TTGGAAGTGT?TTTGGGGGAA?GAAATCTCAG?TCAAGAAACT?16800

AGATAATAAT?AACTATGTCA?GCTAGATAGG?AAGTGCCATC?CCCATGCGGG?GGTCTCAGGA?16860

AAACATGTGA?GGTTCAGCAG?GGTGCAGGAT?GGGAGGGGGT?GACCCGGACC?CACGCTGGAG?16920

AATTGGCTAT?GCATATTCTG?AACAGGATGA?AGAATCAGAG?CCAGCAGTGG?TGCCAACTGA?16980

ATCTGCCTTG?GGCAAAATGT?TGGGTAGTTT?GGACCAGTGA?CCCAAGCTGT?GGCAACCTGA?17040

GCAACAAAAT?AAATAATGAC?AATACTGGAT?ACTCATATAA?TGAAACAAAT?ACCCCAAATC?17100

CCCTGCTGAT?ATAAATACAT?AATTAGTAAA?CAAAGAACAG?GGGATGGTGT?CAGAAGAGAC?17160

AGATCTTTTT?TAAAGGAGAA?TGCATATTAA?TAAATATAGA?AGGAACAAGA?AAAACAGAAA?17220

ATCTTCCTTA?AGTAAACATT?ATAGTAATAA?TTGTTATAGG?CAGGAATTAG?TCATAGATCA?17280

TCAAATTAGT?GGGTAAATGA?TGAATAAGAA?AGTTCTAGTA?CCTTTGCTAA?ACAGGTATTT?17340

AGTATCTTTA?GAAACAGGTC?AAAGGCATGT?ATTACTTACA?AATGGACAAA?TAGCAGCAGG?17400

TCCCACTTTA?ACCAAAGGAC?CAAATTTAAC?ATTAATAACC?AGACACATGG?ACATCTTATT?17460

CCCCCTGATA?TGACGCACTG?AAGATAGGCA?CACTATCATT?TCTGTGGTAA?TTTTGCCCAA?17520

AATATGTAAT?CTCAATCTAA?TCATGAGAAA?ACATTAGTGA?AACCCAAAGT?GAGAGACCGT?17580

CTAAATAACT?GTCTTAAACT?TTTTACAAGT?GTCAAGGTCA?TAAAAGACAA?AAATCGACTG?17640

AGGAACTCTC?ACAAGGTCAA?GGAGACTAAG?GAGGCATGCA?CATTAGATCA?ATGCGGGATC?17700

CTAGACTGGA?TCCTGTTTCA?GAAAAGAACA?TTACTGGGGA?CTTGGAAGTA?CAAATACGTA?17760

TATGGATTAA?TTAAGAACAC?TGAATCCAGG?TTAATTTGCT?GTTTTTGATA?GCCATACTAT?17820

GGTTTAGGTT?AGATATTAAC?AACAGGCAAA?GTTGAGTTAA?GAGTATACAG?AAACTCCACT?17880

ATTTTTACAA?CTATTTTCTA?AGTCTAAAAT?TATCACAAAA?CAAAAAGTTA?AACATGGAAT?17940

GGAGGCTGGG?TGCAGTGGCT?CACGCCTGTA?ATCCCAGCAC?TTTGGGAGGC?CGAGGTGGGC?18000

AGATCATGAG?GTCAAGAGTT?CGATATCAGC?CTGATCAACA?CGGTGTAACC?CTGTCTCTAC?18060

TAAAAATACA?AATATTAGCT?GAGCGTGGTG?GTGCATGTCT?GTAATCTCAG?CTACTCAAGA?18120

GGCTGAGCTA?GGAGAATTGC?TTGAACCCGG?GAGGCAGAGG?TTGCAGTCAG?CCGAGATTGC?18180

GCCATTGCAC?TCCAGCCTGG?GTGACAGAGC?GAGACTGTCT?CAAAAAAAAA?AAAAGGGTGG?18240

AGTTAGTTTG?GCTTCATTTG?GCAGCCAACC?AGGATGAACT?TGGGTGCACA?GATTTCTCAG?18300

GTGAGACCTA?AGACCCTGTC?TCACCTAAGA?AATAAGAAGG?ACATGAATAG?AAACACATAG?18360

TGGACAGGAG?ACAGCGAAAG?GCAGTTCTAG?TTCAATGAGA?GCTTGCGTTG?GGCTGCTTTC?18420

ATTGGACAAG?CATGCCAGAA?TTCTATTGCT?TTATGTGTCA?TGCATCTGTC?CTCCAAGGTA?18480

CTGAGAAGAG?AGTCAGGAAA?GGGTATAGTA?ATGTAGACCT?CAACTGTTCT?TGCCTTCTGG?18540

ACAACAAGGG?ATAATACTTC?CTAGAACAAT?AGCCTCACCC?TGGCACCCCA?GATGTTTGTT?18600

GCCCATTCTA?TCTACAGTCT?CATGGTCAAT?AGTAGTAACA?GCCTCTAACA?GTGAAAAGGA?18660

CTCAGCATAC?AACTGCAGAG?AAGACATAGC?AGAGGGCACC?TGGGAGGCTA?TGACAGTGTG?18720

TTCAGGGAAA?AATGATCCTA?AAAGAAAAAA?AAAACAGTAG?GTGGCTGAAC?TTGGGGATAA?18780

AAAGAGCAAG?CCAGCTTTTC?AGGAGAAAAG?TAGGTCTCCT?AATCAGTCTT?GCAGGCTTAA?18840

GCAGTAAGAA?GACGGCCTTC?CTCAATAACC?TCTTCACTAG?AATTTTCAAA?ACCTAAACAA?18900

ATATCTCAAA?CAATGATTTT?TTTTTTGCCC?AATAAAACAA?TGTCATGTCC?ATAAAAGTAA?18960

ATTTTGAATC?AAATCTTTTT?CCCAGACATA?ATTCTGAAAA?ATCTTAAAAC?ACAAAGTAAA?19020

AGAAATCAGA?TGCTTATCTG?AATATTACCC?ACATGATCAT?TAGAGATAAT?TCTTATACAT?19080

TTATTAGTAT?TCGTCTCTTG?CCAGATATTT?AAATAACTGT?GAAGAGATGT?GTCAAGAGAA?19140

GAGTAATTAT?ACAAAGGTTT?ATAAAAGGAG?ATACAAAGCT?TTATGCTCCA?AATGTGGCTT?19200

TCAGTTTAAA?AACCTAGGCT?GTTTAGCATA?ACCCCAAATA?GTTCTGGGAT?GGTTGTATAA?19260

TATCAGATCT?CAACTAGCTC?TAATAACTGC?TTTGTAACCC?CTGGAATAAT?GCTCGAAGCA?19320

ACACATGATC?TTATTTTGAA?GACAAGTTTA?CCACTACACA?ATGATGCTGG?TCCACACCTA?19380

CCTCCCACTG?CATTACAGCG?AGATGTCATT?TCCCAGAGCA?CCAGAGCCAT?GGAGTAGACA?19440

TCGGTCTGCT?TGAAGGACTC?AACATTCTCC?AAATTCATCC?TGGATTCTAG?GACTTCTGGA?19500

GCCATGTATC?TTGCAGTTCC?CACCTATAGC?AAAAACAGAC?AGTGAGGCCC?ATCATTTAAT?19560

TCCAGCTGCC?TTTTTATTTT?CACAATATAG?CTGATGGTGG?CCCCTGACAC?GTGCAGAGGA?19620

TTTTTTTAAA?AAATCAAAGT?GCTGTTTTAA?AGAATGAGAA?ATGCACAGAA?AGGTACAGAT?19680

AGATGGTTAT?TTTTTAAAAT?AGATGTTCTC?TCCCTGAAAA?CCCTCTAAAG?ACCATAAACA?19740

AAGCATGCCA?AAATAAGGAA?GTGCCAAACC?CCAGAGCTGC?CTTATCTAAC?CCCATGACTT?19800

ATGTCATCAC?ATTTTTCAAT?AACATCCTTA?CAGATAACCT?GAGAGACAAT?ATTTGTGATA?19860

TTTTAAATGT?TTATTTTTGC?TTTCCAAAAT?TGAATTTTTT?TTTATTCCTG?AAACTCCAAG?19920

ACTTATGGTA?AAAATAATAA?TTGCTATCAG?TTTTGATCAC?TTTAGGACTG?AGTCTTAATC?19980

TTTGTTTATC?CCATGGCACA?TTCCAGTGTG?CAAAGGATAT?AGTACAATTG?CATAACATCT?20040

CTACTAAATT?AAATTGTATA?AAAGCATTTT?CACAGTAAAA?GACCAAATCT?GGATCACTTT?20100

ATAATTTTAA?CTTGTGGGCC?ATGTAGTTTT?ATTTTGACTT?TTAGGCCTGT?GCTAATCTCT?20160

ATGACTGATA?ATATGCAAAC?GTCGGATCCA?TATGAAAAAG?GAAAAAAATA?TTCCAGAGAA?20220

TGGCTCACTT?AAATATTTAG?TGTTGTAGTA?TGTATAAACT?GACTAAATAA?CAATAAAGTC?20280

CTACCTTCCC?AAGGATCTAG?GGAAGCCAAG?TGAGTTGATA?TTATCATTCC?AAGGAATGTT?20340

TCTTATTGGC?ATGTATTAGA?GAATTTTTTT?CTTCTCAAGA?GGTCATTGCA?TGGCTCATTA?20400

CTCTGGCACA?TTAGTCTGTC?CATATTTCGA?TGTTTACCTC?AACACTGCGT?GCGCTGCCAT?20460

GGACACAGGG?CTGACTGAGC?AGTAACCGAG?TGCTTCAAAG?TGTGTCCTGC?CACCTGGCTA?20520

AAGAAGACAG?TGCTGCTCTC?CATGGACTCC?ACTGTGTGAA?AACACTGGGC?TCATCATTTA?20580

TAAGGGATGT?TGTGGTGATT?TCCAATCACC?TTCCAATAGT?TTCTTAGCCA?AAAACATTTC?20640

CATTTTAATC?TGTGAGAGTG?CTTCAAGAGT?GGAAGTGCTC?ACTCAGTCGA?CAAGTACTTA?20700

TTTTACTTTC?AATGTTCAAG?GCATTGTGCT?ACATATCTTG?GGTGACCATG?TGGATGTAGA?20760

TTTGGACTTC?AGGGAGATTG?CCTTCCACGA?TGCTTTTAAT?ACAAAGAAAC?CAACACAACT?20820

ACAGCTAGTA?TAGAGCAGAA?AGGACTGAGT?ACAACCATAA?GAGAGGGAAA?AAATAGAGGT?20880

AAAGTACTAA?CAGTGCTTGA?AACAAAGAAA?AAACATTTGC?TGGAAGAGAA?ATGAGGATTG?20940

ATCCAGGAGG?AAAAAATGTG?CTGAACTGGG?AAGGATTTGA?AGATAGGAGG?AGAAATGCTG?21000

TCCATTAGCA?AAAATGCTCA?GGCAGGACAG?AGCAGAGTAT?GCTCAAGGCA?GACTCCATAC?21060

TTTGGCTAGA?TTCCCTAGAC?CAGTGTCCAG?AGTACAGGGC?TGTTTGAGAT?AAGAGCCAGG?21120

AGATATGGAT?CAAGAGGTAG?GGTGAGGCCA?GGCTCAAGGT?AAAGGGGATC?TAGCACTAGC?21180

TCTAACTTAC?CTGCCCACTG?TTAGCCAGGT?CATCCACAGA?CAGAGTAGGG?TCCAGACGCA?21240

GGGAAAGCCC?AAAGTCACAC?AGGCAGCAGG?TTAGGTCGTT?CTTCACGAGG?ATATTGGAGC?21300

TCTTGAGGTC?CCTGTGCACG?ATGGGCATCT?TGGGCCTCCC?ACATGGAGTG?TGATCACTGT?21360

GGAGGTGAGC?AATCCCCCGG?GCGAGGGAGC?TGCCCAGCTT?GCGCAGGTCC?TCCCAGCTGA?21420

TGACATGCCG?CGTCAGGTAC?TCCTGTAGGT?TGCCCTTGGC?GTGGAAGGCG?GTGATCAGCC?21480

AGTATTGTTT?CCCCAACTCC?GTCTTCCGCT?CCTCAGCCGT?CAGGAACTGG?AGTATGTTCT?21540

CATGCTTCAG?ATTGATGTCT?GAGAAGATGT?CCTTCTCTGT?CTTCCAAGAG?GCATACTCCT?21600

CATAGGGAAA?GATCTTGACT?GCCACTGTCT?CAAACTGCTC?TGAAGTGTTC?TGCTTCAGCT?21660

TGGCCTTATA?GACCTCAGCA?AAGCGACCTT?TCCCCACCAG?GGTGTCCAGC?TCAATGGGCA?21720

GCAGCTCTGT?GTTGTGGTTG?ATGTTGTTGG?CACACGTGGA?GCTGATGTCA?GAGCGGTCAT?21780

CTTCCAGGAT?GATGGCACAG?TGCTCGCTGA?ACTCCATGAG?CTTCCGCGTC?TTGCCGGTTT?21840

CCCAGGTTGA?ACTCAGCTTC?TGCTGCCGGT?TAACGCGGTA?GCAGTAGAAG?ATGATGATGA?21900

CAGATATGGC?AACTCCCAGT?GGTGGCAGGA?GGCTGATGCC?TGTCACTTGA?AATATGACTA?21960

GCAACAAGTC?AGGATTGCTG?GTGTTATATT?CTGATGGGGA?AACAAAACAA?GGAGAGAAGG?22020

AGTTGGATGT?GGTAGGTAAG?TACTGTCAGG?AAGTGGGTTC?ATGCCTGAGC?ATCTATAGAT?22080

TTTAGCATCT?GCATAGTTTT?TGTAGATACG?ATATTGTTAA?TTTTTATTTC?AGGGATGCAA?22140

GTGCATGCTC?GTTCAGCCTT?CCCTGCCTCT?GGCCATCTGT?TCGTCATCCC?CTGCTCTTCC?22200

TTCAAACTTC?AGCTTAAATG?TCACTGCTTA?AGAGAGGCCT?AGAAAAACTT?GGAAAACTGT?22260

CTTATTTTAT?ACATTTTCAT?AGCACCTTAT?ACTTTTCCTA?GGTAACAATT?CAGTACAACT?22320

TAAACTAAAT?GAACTATGAC?TCTACCTCTT?GATTTCACAT?CTGTCTTTCC?CTACTCTTGC?22380

CATCCCCCAC?GGACAGGGAA?CTCCATGCTG?GAAGGTACCA?TGTCTTCTTC?ACTACTGTAA?22440

ACTGCACTTA?GCACACAGCA?GGTCCTCAAT?ATTGCCAAAT?AAAAAGACAA?ACCATTTACT?22500

GAGTGTTATC?TAAGCTCAGG?ACATTGGGAA?CATGAAAAAA?AATGACACAG?CTTCTGCCTT?22560

CAAAAAATCT?GCATGTATGA?CATCTGGTAA?AAACACAGAG?CGTGCCACAG?TTTGCACCAA?22620

AATCTTTGCT?CTTTTTCAAA?CTCCAACTTG?TTCTGCTCTG?ATCAGCATTC?AGGCTACCCT?22680

GGGCCCATGG?GTGACAGGGA?GAGGAGTCCA?TGGAAAGGAT?CTCTTTGGAC?AGTTATCTTA?22740

CATCCACCCA?ACATTCCTCT?TTTCAGTGTG?CATACGAATT?GTAGTTTCAT?GGAACTGAAA?22800

TATTTAATAG?CAACAATGGA?AACATGGCCG?CAAAGGTAAA?ACAAGTTAAA?AATGGAAATG?22860

CTGCAGTTTT?TTGACTTGGA?ATTCTGAAGC?AGGCCCCTGT?GGGCTGACAA?GGAGAGTCCT?22920

TAGCACCAGA?TATCTAACTA?TAATATCTTG?TGCCTCAAAC?TTTGTTTCAT?GTGCTGGCCT?22980

TGTTGGCTCT?GGTGAAATAG?TTTTCCTTTT?TGGAAGAAGG?ACATGAATAG?AAACAGACAG?23040

TGGACAGGAG?AGAGCAAAAG?GCAGCTCTAG?TTCACTGGGA?GCTTGTGCTG?GGCTGCTTTC?23100

ATTGGGCAAA?CATGCAGAAT?TCTATTGCTT?TATGTGTCAT?CCATCTGCCC?TCCAAAGTAC?23160

CCATTAATGA?GCAGGCCTCA?TGCTCAGATC?CTAGAATCAT?TCATTAAATA?TATCACTACT?23220

GAGTGTCTAT?GATGGGCATG?GCACTGCCCT?CAGAGAGTAC?CCAGTAGAGG?ACTTAGGGCA?23280

TATATACAAG?TAAGCAATAT?ATGGCATCTG?GGATAGGGGC?TAAATGTACA?ATGTAATCTA?23340

TATATTAGTG?GAATGTGGAA?AAGCTTAGAG?AAACATGGAA?GGCACAGTAG?CAAAAAACTG?23400

CCTTTAAGTT?GGTCTCTGAA?GAATGGGAAA?AGTCAGTGAT?GAGTGGAAAG?AGTGCTATGT?23460

TAAGGAGAAA?GAATATATGA?TCTACTTAAG?GAAGAGCAAT?TATCCCATAC?TGACCACTCT?23520

GCACCTGCGG?AATAGAAAGG?AAAAAAATGG?GTAGGTGGTA?TGGAACCAAA?CTCCGTGTCA?23580

GAAAAGGATC?TTTTGATTAT?TCATTTGTCA?GTTTTCACCT?ACAGTAGGTG?TTTAAAGAGA?23640

AAAAAAAAAG?TGATGAGAAT?ATAGTCCAGG?TAGAATGAGG?ATATAACCAA?ATTCTCTCAA?23700

GGGGAACCCA?TTACCTAAAT?GATACTGATA?AAGGAGTTAA?GAAGAAATTA?CTTGGGCAGA?23760

TAGTAAGGGT?ATGGAAGTCC?TCGGTAAGGT?GTTTCTTTTT?AATGAAAAGC?AGCCCCAAAT?23820

CATTTTCTAA?CAAAGAGCAG?CCTGTAAAGT?TGAGCTTCAG?ACATAGACAG?GCAAGCTGGG?23880

AGCTTGCACG?GGTGAATGCC?AGCAGGAACT?AAGGACATGT?TCAAGATGGC?AGCTCCATCT?23940

TCCCTTCTCT?TTGTCAGCCA?TGTGTACAAC?AAAGAACAGA?CCAGATGGTG?CTGATCAACT?24000

GGAAAGCCCA?TTTGCATAAT?AAGATTAGGG?TGGGGTGACC?AGTCTTCCCC?ATGCACTATG?24060

TAAACGTCAT?ACCTGATTGA?ACCAATCTGT?GAGCCCTATG?TAAATCAGAC?ACCGCCTCTT?24120

CAAACGGGAC?TATAAAATCC?AGCACATTCA?CCACTGGCCC?GTCCTTTCCG?CTTGGAGACT?24180

CCTTTCTCTA?CAGAGAGAAT?TGTTTCTCTT?TCTCTTCTCT?TCTGCCTATT?AAACCTCCAC?24240

TCCTAAACTC?CTCATGTGTG?TTCATATCCT?AAATTTTCCT?GGCTCATGAT?GATGAACCCC?24300

AGGTTATATA?CCCCAGTCTA?CATAGCTACT?TCAGCATCTG?ATACTTTCTT?TTTTTTTTCT?24360

CGAGATGGAG?TCTTGCTCTG?TTACCCAGGC?AGCAGTGCAA?TGGCACGATC?TCTGCTCACT?24420

GCAACCTTGC?CTCCTGGGTT?CAAGCCATTC?TCCTGCCTTA?GCCTCTATGC?CCAGCTTTTT?24480

TTTTTTTTTT?TTTTTTTTTT?TTTTTTGTAT?TTTTAGTGGA?GACGGGGTTT?CACCATGTTG?24540

GCCAGGCTGG?TCTTGAACTC?CTGACCTTGT?GATCTGCCCG?CCTTGGCCTC?CAAAAGTGCT?24600

GGGATTACAG?GCGTGAGCCA?CTGCGCTTGG?CCCAGCATCT?GAAACTTTCA?TCTAACGAAA?24660

CAGTGAGAAA?TGAAGCTGGT?ACATATCCAT?TTTTAAGGTT?TATGTGTAAT?ATGATTACTT?24720

GTTCTTAAGG?TAAGTCTGAG?TGGAAATGCC?AACTTCCACT?GACTATATAT?TCTAGATGAA?24780

AATCTTGGGT?CTAGTAACCA?GAGAAGTAAC?CCCAAGATAT?CAGAATTCCA?GCAACCAAGA?24840

GGGAAAAAAA?AAATCACCAT?TTTTTGGAAA?GATATATGAA?TGCATTTTAA?AAGTATAGGG?24900

AAAGTGAGAA?AATTTGGTGA?TTGATCCTTA?AAAACATAAA?TTCTTACACT?GGGAGGCTTG?24960

GATTGGGACA?AAGAACAGGC?AAGAGTAGGG?CAGAAATGGG?GTGGGACAAA?GCAATTACAG?25020

AATGATTGAA?TGCAAAAGAA?AAAAAAGATG?CTCTTGTGGA?GATGTATGGA?CTGTCCCTGT?25080

TGTACAGCAA?ACAAAATTAA?GGGGGCAGAT?GAACACAACA?CAAATTCAAA?CACAACAGCC?25140

GATCCAGCAG?TCGGCATTTC?CACTTAGGCT?TACCACTTCC?ACAATGCTCC?CTGCCTGAAA?25200

CTCCACCTCT?ATTATATGTG?GTATCCAATG?AATGTGTTTG?CTTGAAGTAC?CCACTTGTCT?25260

CCGGTCTCTG?TGTCTGTAAC?TACATGGAAT?GTCTTATAAT?CAGAAATCCA?CTTGATTATC?25320

TGATTGCTTC?TCTCCTGACA?AAGCAGGGTA?GTGGCCAGGT?CTGTTTTGAT?CATCATGATA?25380

TACACAGCAC?CTGGGGCAGA?ATGGGGCAAT?TTATGGTATT?CAACAAACGT?TTGTTTTAGA?25440

AGCTGAATGA?TTACTTACGT?GGAATGATAC?TTCTCAAATT?TTTTATATTT?TACAGCAAGG?25500

TTTGACAAAC?TATGGCTCAG?AAGTCCATGG?CCTGCTTTTG?TATAGTCCTA?TGACCTAAGA?25560

ATGATTTCCA?TCCCCATTTT?TAAAGAGTTG?TTTAAAAAAC?AATAAAACTA?AGAGGTTCAT?25620

GCAACAGAGA?TCTTATCTGG?CCCAGAAAGC?CTAAAATATT?TACTATCTGG?CCCTTCACAG?25680

AAAAACTTTG?CTGACCCCTG?TTCTAGAGGT?GTTATTTTAA?TAACCTCATT?GGCAGAATCT?25740

GGAGAGACTT?CACTTTGGCC?AAATGTGAAT?ATGTAGTCAA?TTTTTTTTCA?CATATGAGAA?25800

ATACAATTTG?AAAAAATTTA?AATATTAACT?GCATAATTAC?TTAGCTTTGT?CCTTAATTCA?25860

CTAAAACGTC?CAGATGAAAT?GTTGATTCAT?CATGGATAAT?TTTATTTTAC?AATTCCTAAA?25920

TATCTATAAA?AACAGTCGTA?TTTGCTAATT?TCAATTCCTT?TTTAGCCTAA?AGGAAACACA?25980

AAAACAGAAA?TCCCCTTAAG?TTTATGTGTG?GCACTGACTG?AAGAAGATTC?TAGAAATCCC?26040

CAGTTCAATG?TCAGAAACCA?AAGTTTTACT?TTCTCCTAAA?ATTTCCTGTT?ATTTCTTTAG?26100

AAGACTTACA?CTTAAAAAAT?TTGAGGGGGA?GGAATTCTTG?AATAACATCT?GTCAATCTTG?26160

AAACTTCAAA?GAGGTGGTGA?AAAACTCTAA?CAATAGCAAC?CAGGGCTGGA?AGGAAGCTTT?26220

GGGATGTGGC?TTTATCTAAA?CAGGAGCCAC?CCACACCCTC?TGGCAGTATT?AACCCTTGGG?26280

TTGCTACTAG?AAAACCCAAC?AGCTGTTGGT?GTAGGTACAA?GCCAGCATCT?CCTTTAGTCG?26340

AAGACCAACA?GGAAATGCTT?CTTTTCATCA?GCCGCCAGTT?ACAGAGAAAC?TCATAAACTG?26400

AACACTTACT?AAGTTCCTGG?CTGTGTGCTA?AGGATTTTAT?AGAATATTTA?AATTTAATTG?26460

ATAGAAAAAC?CCTATGAGGT?AGAAACTGCT?ATTATTATAA?ACCCCATTTT?ACAGATAGGG?26520

AAGCTAAAGA?TCAGACAGTT?TAAGTAATTT?TCCCAGATGA?TAAATTTAGG?CAACAGCAAA?26580

GCTGGTATTT?ACAATGAGCA?TTGCCTGATT?GGAGAGACTT?CTGATCTCAA?CCCCATACCT?26640

GATCTCTAAA?CTTCATATTG?GTGAGAGCCA?ACTAAGAATG?GCAATGACCT?TAGGCTGGGT?26700

GTGGTGGCTC?ACACCTGAAA?TCCTAGCACT?TTGGCGGGAG?AATCACTTGA?GCCTAGGAGT?26760

TTGAGACTAG?CCTGGGCAAC?ATAGTGAGAC?TGTCTCTACA?CAAACTTAAA?AAAAAAAAAA?26820

ATTAGCCAGA?CACTGTGGTG?CTTCCTGTAG?TCCCAGCTAT?TACGGTGGCT?GAGGCAGGAG?26880

GATTACTTTA?CTTGAGGCAG?GAGTTCAAGG?CGGCAGCACA?CTATGATCCT?GCCACTGCAT?26849

TCCAGCCTGG?GTAACAGAGC?AAGACCCTGT?GTTTGTGCGG?GCGGGGATGG?GGGGGTAGGG?27000

GTTGCGGGGG?AGGGGAAGAA?TGACTTTATA?TAAGCTCCCA?ATTTGATAAA?GTGTTTTTCT?27060

TTAGTGTAGC?CTGGACTAAG?TGATTTTACA?GCCATCCACC?GACTGACATT?GGCAATTCTT?27120

GTATAATGTG?TCTAAAGGAG?TATATTTTGG?GTATGGGGAT?TATATTCCTT?TGTTCTGAAC?27180

TAAGAACCAC?AGTTTAGTAG?TGTCTCTGTA?AATATGCATC?TTTTTCCTGC?CAGGAAATAA?27240

AAAGTTTTAT?GTGAAGGAGA?ACCCCCAAAT?CTTTTTCTTT?TCTCAGAGCC?TATTCTCATG?27300

GCCTAGATCT?TAGCAGAGCT?CAAAACATAA?TTGTTGCACT?ATTGGGACCT?TCCATGAATA?27360

GTAATAACAT?TGAACCAGAT?ATAGCTCTGA?AGGGCATTAA?AAATAAGGGT?GGAATTTATC?27420

CAAGGCCCAT?AAAAAAATGA?GGCTATAATA?GTAAACATTT?TTAGCCTGGG?TTCCATAAAT?27480

AGAGTTCAGT?GGGTCTGTGA?ATTTGAATGG?GCAAAAATTG?CATCTTTTTT?TATTTTCTCT?27540

AACCTTTAAT?TAAAAATTAA?TATTTCCTAG?TATCAGCTGT?ACCTATGAGT?TTGTTGTTGC?27600

AGACGTCTCA?GCATGTGACT?TACGCTCACC?ATTTAGACAT?TTCAATTGTT?TAGATCTGCT?27660

GCTATTGTTA?TTTAAAGCAT?TATTATAGAA?ACATATATTA?CTATAACACA?AATTCATTTT?27720

TAAAATATTT?GGTCATTGTA?TTTCAATGTA?ATTGGTTTTC?TTTGAAATAC?TCCATGTTCT?27780

ATTTTATGCA?TTTAAAAAAC?ATCACAGTGA?GAAGGGGTCC?ACAGGCTTCC?CTACTTCAAG?27840

AAGTCCATGG?CACAGACACA?CAAAAAGGGA?AGCTCCCTTG?GCAGAGTGAA?GGCATTTGGG?27900

CTCTAGTCTC?TTTTCCAGGA?CTTGCTAGAG?CAGGAATTTT?GAGATTGATG?GGTTTCTCTA?27960

GGAAGTTGGT?AACTAGTGCC?AATGGGAGAT?CTGCCTGGCT?TGATTTGTTG?TGCTGCACAT?28020

GGACAACTGT?GGATGCTGTC?GGAGCTTCTG?TGGAGTGGGA?AGGGAGCTCC?GCAGTGTAGA?28080

ATTTGAGGAG?AAGCCCTCCT?TTGAAATCTT?GTAACAATAA?GAAAGATAAC?TCATATACGA?28140

TGTGCTTTGT?TGGGTTAGGC?ACCGGACAAT?TTATTTTGTA?AACATGATCT?ACTTTATTTC?28200

TCCAATAACC?CTATGTATGA?GTTAGATTCT?CTTACCCCCG?TTTTACAGAG?GAGGATACTG?28260

AACCTTGGTT?GCTTCTACAA?CATTTTTGTC?TACTTAGTAA?ATAAGTATTC?TTGTTAAGTA?28320

AAAGTTGTTC?CTAGTAAGTA?CTCAATAAAT?GAATGCTGTC?CTTTTAATGT?TATAATTAAC?28380

ATGACTTGAG?ACAGGAAGTT?CTTCCTTCCC?CTCAGCTATC?TCTCTTTAGC?ACAGTTTCCT?28440

TCTTTGGATC?TCAGCCAGTT?GCATATATAC?TCTCGCTTTA?GGTGAACATG?CTGGCATGTG?28500

AACATCCTTG?CGGCTAGAGC?TTCACTGCCA?ACTTCACAAG?AATCTCTCTT?GGCATCTGAG?28560

GCTCATTAGT?GCACTAATAC?ACCAAGGTGT?GCGAAAAACT?GTCATCCACG?TCCCTTTCTA?28620

TTGCTCGGAT?AAATTAGTAT?CCCACTAAAT?GTTCACCCTA?AACTCCTTTA?CCGAGTGGAG?28680

GAATTGCCAA?ACTACTTCAA?ATATTAAAGT?AGGAGCCTAT?CTCCCAAATT?CAGCTATGTT?28740

GATTTGCTTT?TTATCAAGAC?ACATTAACTG?ATCCACATAG?GATTTTATTT?ACCAAGTTGG?28800

CCTTAATTTA?ATGCTTTTAT?TTTTTTAACC?AAGTGACTTT?TATTTAAAAT?AGTGGATTAG?28860

GGAGGTTCAG?TTTTAAGTTC?CTTTTAGGAA?CTGGTGTCGG?CATAACAAAG?GACATAAAAG?28920

AGGCTGAGAG?CAACGTGTGT?GTGCGCGCAC?GCGCGTGTGC?ATGTGTGTGC?GCACATGCAT?28980

ACTCAAGTTA?TAAGACAAAT?TGTTTACTTT?TCAATCACTC?CAAAGGAAAG?TATACCACAG?29040

GATTTCCCCT?TGAGGTTTTC?TGCCAGTTTG?TATTTTTTTT?TATGGCATAC?TAACATTTAT?29100

CTTTGGAAGA?CAGAAAAAAA?AAGAATTTGA?CATTTGTCTT?TAAAAAAATA?TTTATGTAAC?29160

AAGACTCTGA?CATTTGCAAA?TGGCTCCTTA?TTTGCAACTA?AGTCTGGCCT?CTATGAGTGA?29220

CAGAAGTGAC?TGGAAATTTT?CAGAATTATT?AAATGGATCT?CACAGTTCAT?TGTTAAGGAG?29280

ATAGCTTGGT?GGTATGGAAA?GAACAAAAGC?TTTGAAGCCA?CTCAGATGAT?TAAAAAAAAA?29340

TGGGGGGAAG?ATATGGTGCC?TCACACCTGT?AATCCCAGCA?CTTCGTGAGG?CTGAGGTGGG?29400

AGGATCACTT?GAGCCCAGGA?GTTTGACACC?AGCCTGGGCA?ATATATTGAG?ACCCTGTCTG?29460

TATAAAAAAA?AAAAAAAATT?AGCTGGATGT?GGTGGTGTGG?GCATGTAATC?TGAGCTACTT?29520

AAAAGGCTGA?GGCAGGAGGA?TCACGAGCCC?AGAAGTTCAA?GACTGCAGTG?AGCTATAATG?29580

GTGCCACTGC?ATTTTAGCCT?GGGCAACAGA?ACGAGAACAT?CTCCCCCTGC?CCCCCCAACT?29640

CCCCCCCCCA?AAAAAGTTAG?CCCTCTCTTC?CTCTTTCCTT?TCTCCTAAGG?GTATTTAAAA?29700

TAATATACTT?GGCCCAAGAG?CACAGTATGG?CCCTCAAAAC?TAGAGAAATT?ACTCTGATTT?29760

CTCTCTTGTG?AAAAAGAATT?CATTCCAAAA?TAAAACACAG?ATACAGAAAA?GTGCATAAAA?29820

CAAGTGTCTG?GCTTAGTGAA?TTACTATAAG?ATCAACACTC?TTGTAACCAC?TGGTCAGGTC?29880

AGAAAATATA?ATTTTGCTGG?CCACCCCAGA?AGTCTGTTCA?TGTTCCCCAA?CTCAATCGGA?29940

GATCCCTCCC?TTCCTCTAAA?AAGTAATCAC?TATTCCTGGC?TTTTATAGTT?ATCATTTTCT?30000

TGAGCTTTTA?AACTTGTTTT?ATCATCCAAG?TATGCATCTG?TAGTCGTCTT?GCTACTAATA?30060

TGACTGAATA?CAAATGGCAA?ACCTTGCTTT?TTTGCAGAAT?TACTGTTTTA?AAAAAACTTC?30120

CTACAATAAA?AACACCAGAA?TCTTTAAAAA?ATGTTTAATC?TGAATTAATC?AAATCATCAG?30180

ACAAATCTAC?AAAGTGCCTT?TATAAAGTAC?ATGAAATGGT?CTGACCTATT?CAAATCAAAG?30240

TCAATGTCAT?GAAAACCAAA?AAAACACACT?GTAGAGGCAA?AACAATCAAT?TTTAATGTGT?30300

TGTCCTTGAC?TGGATTCCGA?ATTTAAACAA?TAGACCCATT?AACCTTGAAG?AAATCTGAAT?30360

ATGGACTGTA?CTGTATATAT?ATTTAGATGT?ATATATGTGA?ATGTATCTGT?GTCTTAGTAT?30420

CTGTATACAC?ACACACACAC?ACAGAAAGAG?AGTGAAAGCT?AAGCACTCAC?ATATATGCTT?30480

CATATTGCAG?AGTTCAAAGA?TCTTGCCATC?ATTTTCTGTA?CCTTTAAAAA?TTTTGTTGGC?30540

ATGTTACATA?AAGAATAACT?TGTCACCTCG?TTATTCTAAG?TGTGCCCGCA?GACCAGCAGT?30600

CATCAGCATC?CCCTGGGAAC?TTACTGGAAA?TGCAGAGTCT?TAGCGCTGTC?CTCAACTAAC?30660

TGAATCAGAA?TCTACATTTA?AAAGTTCTCT?CAGTGATTCA?TTTACACATT?CAAGTTTCAG?30720

AGGTAAATTT?TATTCTTGCT?AAACAGTTTA?GCAAAAATAA?AGTTAAGTTC?TTTGGTACTC?30780

TGCCATAGAG?ATGCTTTCCT?CCTACAAAAA?ATTTCTTAGT?GGAATTGTTT?GCAAAGCTCT?30840

GGTACAGCTG?TATTCAGCAC?TAGCCAATGA?GAAAATGGCC?CATGATAATT?TTCTAGTCAA?30900

TTAACTGGTG?GAGGAGTGTA?GAATGAGATA?TGCTTCCCCA?TCCATCATCC?TAGTAAAAAG?30960

CACACCAATT?TAGGCAAACA?ATAAAAAGTC?ATTTCAATTA?AACAACAAAA?GGACAGTAAG?31020

CTCACTAGCA?ATGAAGGATT?TAATTTAACT?TCTAGCTATT?GATAGCACTG?TTTGACATTC?31080

TGGATATATT?TTGAGAGTAT?TTTTTCCTCA?AATGATGAAA?GAAGTCTTCT?CTCCAATCAA?31140

TGTGGTTGTT?TTATTCCAAC?TGCACATATT?TCAGAACAAA?GCTATTCGCC?ACCTCTCCTA?31200

TCCCATGGCA?CAGTCTCCTT?TGTATTATTT?CCTTCTTATC?TCTCTCCCAG?ATGGAAAAGC?31260

CTTGCATGTA?TTCTAATCCA?GTATGATAAT?CTCTTTCTAG?AATACCCATG?AGAGGTAGAG?31320

GTGAAACCTC?TGCCTGAAAA?TGTTATGGTA?GAAGGACATC?ATTCCTTTGT?TATCATTCCA?31380

TAATCAAATC?ACAATATTTC?TAACTGCAGA?TATATTGGGA?TAAAGTCTAA?ATATTGGGAT?31440

ATGTTTAAAA?TTATTCTTTA?CATTAAGTCA?AATGTAGCCT?CTGTGTGCTT?CTATTATTGG?31500

TCCTTCTGCT?GTTCTCTAAA?GCAAAAAGTA?ACAAAATGAA?TCCGTTTTCT?ATGGGATGAG?31560

AACTATTAAA?CTCCTGCTGG?ATATGAAACT?CACAACCCCT?AGATCATTTC?ATTTTCAGGT?31620

TGAACAGCCA?TGTTTTCCTC?GGTTACTTTT?CAAGAGATAC?ATTGATGAGA?CTCTAAAGTC?31680

TGACAGATTT?ATCAGACCCT?AAAATCAGCC?TGCCCAGCAT?ATAGCGCCCA?ATAAATGCCA?31740

GGACCTTTTT?TCTAAGGGTA?AAGTGATCTG?TTCTCTGAAA?CCACGCTTGC?TATTTAAGAT?31800

TCTTCATCAT?GTGTTTTGAT?AGACACAGAT?ATAATACTTG?GAATATAACT?TGTGTAGCAA?31860

AGATTACAGC?AGGACTCTCA?CCTCCTCTTC?CACCAAGTGG?AGTTTAAGGC?TCCTGATGGT?31920

TTGTTCTTTC?TGTTTTGTTT?TGATTCTTTC?AGCCAGATCA?TCCTGATTTC?AAAATGACCT?31980

TAACTCACCT?CTAAACCCTG?GGGTCTTCAT?CACATGAGCA?GATTCCCAGC?CAGTGTTTTG?32040

ACAAGTGCTC?CTTTGCAATC?GATTGTTTGA?ACCTATATGT?CTGATTTTAC?ATCTACCTGT?32100

CAAGTTTTAG?AAAATTGGTC?ATTTCAGGCC?ATTAAAACCC?TGATTCAGCC?TTTGCTCTTT?32160

TAGGCATCCC?TTCCACTGTG?CTTTTCACCC?TTTATGTTCC?TCCTTAGGAT?ATAGATTCCT?32220

GCTACTTCTC?TTGCTCTGAC?TTTAAAAGGA?GGGCAACCAA?CATTAGGAGG?GTGCCTACAA?32280

GGTACCAGGC?TTTGTCCAGG?AAATGATGAC?ACATCTGTCC?TCCCACAAAG?AGAGTTTCAC?32340

ACCTGATATA?TGTTCTTTGG?AACAAGATTT?TTTTTCATTT?TCTTTTCTGT?GTTATTGCAG?32400

TTTTCTGACT?ACTAAAAGCT?TAGGTTTTGT?TAGGATCCCC?ACACCTGCCC?TGATTCTTTA?32460

ATTCTTTTTC?TGGCTGGCTG?TCTGAATTAC?ACCTTGTACT?CTGTCTAGGG?GCCCTCATGT?32520

TCTCAGGAAA?CCTGAAAGCA?AGGTACATTT?CTTAAGTTAT?TTCAGGATGC?TCTCCAACAG?32580

GGAGACCAGA?TCGCTTTGGA?AAAGCATATT?CATTATTCAC?AATACCTGTT?AGGTCACCAG?32640

AATACATCCT?CTCTCTCTCC?CTGGCTTTCC?AGGTGAACCA?CAGGCTTCTG?CAATTCCTTC?32700

CCACCTGAGT?TTCTCACCTC?CTAAAATCAT?GCACACAGCC?TCCCTGGTCC?CTGCCTTGTC?32760

TCTGCCAAGG?CAGTAGCACC?CAAACCTTGC?CATCCAACCT?TTTGGACACA?TTAAGGTTTA?32820

AAATGTGCTT?TCCTTTAACG?TATAATTTAA?TCAGTTTTAA?AAGCTAAGAT?GCCTATTCCC?32880

AATGAGGCCG?TTGACCTTGT?TCCAAAGCAA?TTGCTTGTAA?ATTGTTGTAG?AAAACAAAAT?32940

AATATCCCCT?CTTAAAGTGT?CTTGCTATTC?CTCCAAGGAT?GGGGTAAAAC?AGGTGTTGGT?33000

TTTTCTCCTC?CTCTAACCTT?CGAAGGCATA?ATTTTGGCTC?CTTCCTGTGG?TAGCTGCCAT?33060

TCTTTAATTG?TTACCGTCCC?TTTCCAGGCT?ACAGGGGGAA?CGTGACGAAA?AATATAAAAA?33120

GATTTGGCAG?AACAAACTGT?CTTGAGTCCA?GTGGTTCCCA?ATGTGGGCTG?CATATTAAAA?33180

TATCTTGAAG?AATTAAAAAA?TAATTCCTGA?TACCAGGCCC?CAGACCAATT?AAGTCAGAAA?33240

CTGCAGGAGT?AAGACCCAGT?TAATGAGTAG?TTTTTAAAGC?TACTCAGGTG?TTTCCAATGT?33300

GCAGCCAAGC?CTAAGCATAA?CTACATCAGC?CTGGTGGAAG?AAACAGGTAT?TTCGAATAGG?33360

ATGGGGCCTG?GAAAATGAAA?GACATGGGAA?TAATTTTAAT?GACTACATTT?CAGAGAAATT?33420

GT7CTTGACA?TTGGAACCAA?CTATATCCTC?TAATTAGGCA?ACAAAAGGCA?TATATATGTA?33480

TATTTTTAAA?AGTAGATAAG?CAAATATAAA?TTATTTCTCT?AAAAGTTAAC?ATGTTTTTAA?33540

AAAAAAGCAT?AATTTGTAAT?GGCAAAATTG?ATATTTTCCA?CAACAGGTAA?CATGCAGGAG?33600

CGATTTAGAA?TACAAAAGGA?CTTTCCAAAG?GCAAGTCATC?CAGATGTCCA?AATGGTGGTG?33660

AATACAGCCT?CTGGAGTATA?CGTGGGTGGA?AATAAAAGTC?AATTTCACAG?TGGTTAGCCA?33720

CCTCCCTGAG?CCTTTTTTTT?CCCCTGGTGG?GACACTGAGA?CACTCGCAAA?GCAGCAAAAG?33780

GTCTCAGTGG?ACCCTTCTTG?CCATTACTCA?TGGGTGTGGA?GTTTATGGAA?CACATGGAGG?33840

CCGCAGTGGG?AGAGACCTGA?GGCTGCAGAG?GAACCACCCG?AACCTTGCTA?CAGCACCAGC?33900

AGTATGGGTC?CGACTGCTTT?CTTGGCCACT?CATATCCAGT?GGATGGAATT?TGAGACAGCC?33960

TGTGTCCATA?CTAGATTCCA?CTCTGCTGAT?TCATACCAGA?ATGAGGTTCT?AGAGTACAAA?34020

TATTCACAAC?CAGAAAGCAC?ATCTGGCCTC?AGTGCAGCTT?TGTTTACTTT?GCTACTTAGG?34080

AAAAAAAAAA?ATCTTGAAAA?GCGAGTTGCT?TTTGCCTTAA?TTCAGTTCAA?ATACATTCTA?34140

AGCTTCCTTC?AACTGAGTCA?CAGTGTCCTC?TATCATGCAA?AATCTTTATT?ATTTCCTTGG?34200

CCAGACATAG?GGCCATATTG?ATGAATTCCA?AGTGTGCTTT?CTAACCAAGG?CTGGTTCACA?34260

ACAAAAAGCT?GCTTCAGCTC?TGAGTCATCA?CCTCAAATAA?CTGATTTCTC?TTCTCAGGAA?34320

TGAGACTAGC?AACTTTAATC?CATAATTTTC?TTCCTCTTCT?AACAACTTTT?CTCAACCATA?34380

TTTCCACACT?TATTTTTTCT?TCTGCATTTA?GACCAGAAAG?TAAATCTGGT?TTGTTTCTTT?34440

TGAAACAAAA?ATGCACAGCT?GGAAAGCCAG?CTATTTTGAG?GCGTGAGTGC?ACAGTTCCAA?34500

GGCAGCATAC?CTAAAATCCC?CCAGAGCTAC?CAAAACACCA?TTTACTCTTT?TCATTTCTTA?34560

CATGCAAGAA?CTAATCATTT?CCCCAAGAAG?CCAGCTCCCT?GGTGTTGGAG?CTGAACAAAC?34620

ATAAAATGAG?ATTTGGGAGA?AAGAGGGCAG?CATTTCTAAG?ACTTCCCTTA?CTCGGAAAAC?34680

AACGGAAGTC?AACAAAATGC?TCAATGCATG?CGATCAGTAC?ACAGAGTGGG?TTTGCTGGAT?34740

GGTGTAAAGC?AACGACATTA?AGGACACAAT?GGGTCCAGAG?GGAACCAGCT?GGCTGAGATG?34800

TTCTGCTAGC?AAGTTAAACA?TAGACAGGAA?ACCGCGTGTC?TGATACTGTA?AAAAAATAAT?34860

TTGTCTTCCT?GCCAGAGATA?GGCTAGCAAA?CCAAAAAGGC?TGTTTTCACT?TAAAAGAAAT?34920

GCTACAACAA?TGAGAGAGGA?AGGAATGAAA?CTTTGTGGCT?ACAAGAAGTC?TTCTTCTCTG?34980

CCCCTCTCTC?AACATCTCAG?GTTAGAGGGC?ACACATCACC?ACACTAAATG?CTAAAGCCTG?35040

CACATAGCTT?GCGAGTCAGC?AACGTGCACC?ACTGGGCATA?CATCTTATGG?TCTGCTTCCC?35100

TATTTAACCA?CATAGATTGA?ACTTTGAGTC?AGAAGTGGTT?ACTCAAGTCC?TGGTTTCTAA?35160

GCTAGCAAGA?TATAATTGAT?TTATTTACTT?ACAGTCCTAT?CCCATTCCCA?AAAACAACAA?35220

CAACGACAAC?AACAAAAAAC?ACAGTGAAAG?AAGATACAGT?CAAGACAGGA?GCTATAATTA?35280

TGACAAATGG?AATATAAATG?TGAGAAAACA?GGGTAAAAAC?TGGTAAGCAA?GAGTGATATT?35340

AGTATGCTAA?ATGTGTAGGT?ACATATTTGC?TAGAAGCATG?ATTCAGATTT?GACTCTAAGC?35400

TTTTCTGGTA?GTTAGCATTT?GAGAGAGAAA?CACAAAAACC?ATGAATATCT?CTATCAGGGG?35460

TTGGCCTGAG?CCCTGTTTTT?GTAAATGAAG?TTGTACTGGA?ACACAGCCAC?GTCCAATCAC?35520

TTACACACTG?TCTGTGGCTG?CTACCACAGA?AGAGTTGAGT?AGCTGTGACA?GAGACTCTGC?35580

CCTGCAAAGC?TGAAAATATT?TACTATCTTG?CCTGTTATCA?AAGAAGTTTG?CAGACCCCTG?35640

CTCGGTATGC?TTCAAAGTGT?CCTTAAGATC?AGAGGCAAAC?AGGTCGTCAT?GAGGAGAACA?35700

CCTTTCTAAA?ACAGAGAGCC?AAAATAAATG?TCTCCTGGCT?TCCTCATGAA?GATAACAATA?35760

CAATGCAGTG?AACAGCATCC?TCCACATTCT?TTACAGTAAA?CATACCACTT?TGATTCACAG?35820

GACTCCTTAT?AATGGGGAGC?ACCTCAATAG?GACTCAGGTG?GAGGAATTTG?CAGGGAAGAG?35880

GAGAATACAT?GACGTTGGTA?CAAATCTCCT?CACTCATCCA?GCTAAAGGCA?AAGATAAGAA?35940

ATTTGAATCT?AGTGGAACAG?TAATAACTAT?TTACAGTCAA?AATTCATTAA?GTGCTCACTC?36000

TGTGCCAGGT?GCCGTGCCAA?GTTCTCTACA?TAAATAAATA?CATTTATCCT?CAAAATAATC?36060

CTATTAAAAG?TATTCATTAT?TTCTACTCCC?ATTTTTCAGA?GAGGTAAACA?AGTAGTTACC?36120

CCAAGAACCA?AGAGCTTACA?CACGGCTGAG?CTGGGATCTG?AACACAGGCA?ATCAGCAGGG?36180

AAGCCATGCT?CTCAGCCCTG?CCCTCTGTTG?TCTTCCCAAC?AGATGAGCAT?CTTACTGGCC?36240

ATCGTTTATA?CACATCATTT?CTCACGGACA?TGGAAACAGT?GTCAGCCTGA?GGTTGTGCCT?36300

CTTGCCAAGG?ACATGCTCAG?TGATGGGTCT?GGGCTGCCGT?TTGGCAAACA?GAACAGGTAG?36360

CCTCTTATGT?AAGTTGTGCA?GCCTCCCATG?GGTTAAGACT?GATAAAAAAG?CAAACACACC?36420

ACCACCACGG?GAATGTGGAA?GGGTAAGGGT?ATTCCTTCTA?TAAGAGACAA?GATTATCTGG?36480

TTCTTCTATG?ATTCTCCTAC?GGACAAAAAG?TGAGGAACAA?ACTATGAGAT?CTTGGAAAAT?36540

CCCAGCTCCT?CTCTGGAGAC?CCACTTTTTT?GTCATTAAAA?TGAGAAGTCT?GGAGGAGCCA?36600

ATTCACGGGT?TTCACTTCAT?CATAAAAATG?TAATGAGTCT?ATGAAACAAG?ACAACACACC?36660

TGAAAGTAGT?TAGCACAGGT?GCACACATTC?AGAGTAGGCT?GCAATCCAAG?GCAGCGATCA?36720

TCACTATAGT?TGTTCTATGA?GTTCCCACAG?CCTAGGCCAT?GGGCTTGCCA?CCACCTTGCC?36780

TACATTTCAA?TTGGAAAAGG?GGTGGGACCC?TGGTCCTGCA?AACAAACTAC?TGAAAGTCTA?36840

GGACTTGGGT?CCAATGCTAT?CCCTTTCCTA?TATGGCCCCA?GTGCCTCTCA?TTTTCTAGAA?36900

TAAGCAGTTC?AGTTCTAAGT?TAGCAGGAAA?AGCAAGATGG?CCAAGATCCA?GTCATTTGGG?36960

AGCTGGAAGT?GGTCCAGCAG?CATGCCTCCC?TTCATCCTCC?TTGGCTTACC?ATCTTGTTTT?37020

CCACGTACCC?ACCTTCAGCA?GACAATCTTA?GCAAACAACC?CAAGAATGAA?CTGATTCAGG?37080

CCAACTCTTC?TTAGAACCAC?ACTATTACTC?TCCAGGGCTT?TCCAAGGCCA?CCAAACATCT?37140

CCTTCATTGA?TCCAGTTCAA?AACAGTATCT?TGTACAATGC?ATCTTGAAAA?CATTCGCAAA?37200

TGTCTTCTTG?TTTTGGGAAA?TATTAAGGGA?TAGTCCCACA?GATAAACTAA?TACAAATACA?37260

ATAAACTAAC?ATGAACATGA?TCACAGAAAC?AAAAGAAATG?CTTACTGAAA?AGGTGTCTGA?37320

TTTTCTCCAC?ATTAAGATCC?ACACCAGAAC?AACATTTGTG?GAGTATATTT?AAAAAATAAA?37380

CTATTGTCAC?TGCTGAAAAA?GACCCACATG?CCACTGGAGA?GCTCTGTTAC?ACAAGCTGAC?37440

TGAGTAAAGT?ATATTTAGTT?CATTTCCAAA?TGACCAGGCT?TTAGACCAAA?TTTATTCCTC?37500

ATGGGCCCAT?TAGCTCAGGG?AGTTACCAGC?ATGAAGTTAA?TAAGACCTCC?ATCTCTGGTT?37560

CCATCCCTAC?CTGGTGAGTT?CACACCAGTG?CTTCTCACAC?TTCAGTGTGC?AAACAAATCA?37620

CTGAAGGCCT?TGTTACAGGC?AGATGCTAAT?GCAATAGGCC?CCAGAGGACC?CAAGGTTGTG?37680

CAGTTCTAAT?AAGCTCCCGG?GTGATCCTGC?TGCTGCTGGT?CTAGACACTT?TCAGTAGCAA?37740

CGGTTTATAC?CGTTCAGAAG?AGGTATGTGT?CTTGGTGTAG?AGTGTTCTCC?TTAATCAGGG?37800

GAAGAAGAAG?TAAGAAAGGA?TGCACCTACT?GTGTGCCAGC?CACTGTGCTG?GGCGCTCCCA?37860

AGCATCATCT?CCTTAAATCC?CACAACAACC?CACAGGTACC?ATTTATCAGC?ACTACTTGGC?37920

CAATAATGGC?GCAGTCATTC?AAAGAGAAGG?CCTTGTGGCC?CAAAGCAAGC?TTTCCATGGA?37980

AAAAATGAAG?AGGGAATGAA?TCCCTTTGGC?AAGTACAGAA?CTGCGATTAC?CCTAATCACT?38040

TATGTGAAAG?GCACTTGTGG?GTTGTTTCAG?TTTTATTTAG?CTGCTTCCTG?CTGTGATTCT?38100

GAGTCAAAAC?AGGAACAACG?TGTCTAATTT?GTAATATTAT?CCAACAATGA?CAGGGATGTG?38160

GTTAGCTTTG?ATTAGAAATT?CTAGACTCAG?CATGCTCCCC?TTGCCTCTGT?GAAGGCATGT?38220

GGAGAAAAAG?AGAAACTGGA?TGAAACAGGG?ATTAAAGCAA?AGTGAGCCCC?TCCAAAACCT?38280

TGTGGTGTGA?TATGTAGGTA?TCCGAATGCT?CAGTTTATGC?ACCACAGTCA?GCACTCAACT?38340

ACAAAACTTC?AGTGTTAGAA?CAGACCGAAG?GCTACACAGG?CCTGGTTTCC?TGCATTCAGA?38400

CAAGCACAAG?TCACCAGCCC?TCTATAAAAA?GCCCAACTAC?TGCTAACAGC?TAACAGACAG?38460

TGACATGTCA?GGCAACGTTG?CAAGCACTTT?ACATGCATTA?ATCTACTCAA?TCCTCACAAC?38520

ACCTCCCACC?CGCTTTGTAT?TTCCATTTTA?CAGATGAAGA?GACTGAAGCA?TGGAGATGTC?38580

AAGTCACTGG?CCCAACATAG?CAGAGCTAAT?AAGCTGTAGA?ATAAGCCTTA?AATCCAGGAG?38640

ATCTAGCTCA?TTCTTGAGTA?TTACACTAGA?CCGTTTCTCT?CTTACCTAAA?CCAGCAGAAA?38700

TCACCTCTTC?GCTCAGTGTT?CCACAAATTA?AATGTCTGAC?TGCACTTGGA?AACCATTTAT?38760

GAAATGAATA?AAACTGAGTT?GTTGTGTTTG?ATTCTTACAG?GTTCAGTGAG?AGATCAATAA?38820

CCATATCATG?TCTTTGCAAA?GTGGGGATGT?CATTGGCAAG?TAAACAGCAT?GGCTATTTGC?38880

TCAGGATTCC?TTCCTCTCCT?ACCTCCTGTG?CTGCTGCCTT?CAGTCCTGGT?GCCCATCAGG?38940

TCTCGTCTGA?CTGACAGCTG?TCACCAGGCC?ATCCATCATG?ACCAATCCAA?ACAACTTCTC?39000

TTCTAATTGG?AATTTTATAT?GTTGGTTAGT?ACAGGGATAG?ACTCTGATTT?CCTTAGAATT?39060

CTACACAAAA?TGTTCTGGCA?GGAGGGAATC?TTCAGAGACT?GGGAGGGAAG?CATGAATGTG?39120

AGAGAACAGT?TGTGCAGTGC?AGACCCCAGC?CCCATTCTAG?TTGTTTCTTG?ACCCCTGCCT?39180

GCCCTTGGTC?ACTGTAGGGA?GGCAGGGGAA?CTGGCACTAG?GCCCCACTGA?GGGATTCCAG?39240

GGTTAAGGGT?AGGTACCCGG?TTCAAAGAAA?AAAACAGCAA?GGTTTCTTTA?ACTCTTTCAT?39300

TCTAAAAACC?ATGATCTCAG?TCCTCTGAGG?AAAGGGCATC?TATGACACCA?GTGTCTGATG?39360

TCAAGATGTT?ACCGTGTTCC?TCTGCCTCTA?CAGACAACCA?AGCCTCATTT?ACAACAACAA?39420

CAAAAGGAAC?AAATGTTAAA?TCTCTGCACC?ATTTTGTCTA?GATGTTTGAA?TTTGTCTAGC?39480

ATTTGAATTT?TTTATCATAT?GCATATATTA?TCTCTTTGGA?AACATACAGA?GATATAAAGA?39540

GAAAGAAGGA?AATAAAAAGA?GGAAAAAAGG?AAAGAATTAA?AAAAGGAAAA?AAGGAAAACC?39600

TTCACAGGTT?TTAGTGCCTT?ACATATCCCA?TTATAAATCC?TAGCTTTGAT?ACCCACTAGT?39660

TGTTTGATTG?TAGACAAAGT?GTTAAATTTC?TCTAAGCCTG?GTTTTCTCAT?GCATAAACAG?39720

GGATCCTAAC?AGTGCCTACT?CGCATGGGGT?GGCTATAAGA?TTAAATGAGG?TCATGCTTGG?39780

AAAGGGCTGA?GCTCCCTGCA?CAGCGACAGT?ATGTTTTCTC?TGAATATTAA?CTATCATTAA?39840

TAGTAGCACT?AGAAATAAAG?ATCCATACTT?AAAATCTTGT?GGCTCAACTT?TTTTTTCTTA?39900

CATATTAAAA?AAGGTAGATG?TACATAATTA?TCATCCATTG?TGTAGCTGCA?GATCAGGAAC?39960

TTGCCAACAA?GAGTACTGTA?CTACTAATAA?TACAGCCACA?ATGCACTTCA?TAGCTTTTGT?40020

GTTCACCACC?TTGTTGGACT?TGGAGTAGAC?AAATCAACAT?TAAGAGTTTT?CATTCTGGCC?40080

GGGTGTGGTG?GCTCATGCCT?GTAATCCTAG?CACTTTGGGA?GGCTGAGGCA?GGTGGATCAT?40140

CTGAGGTCAA?GAGTTTGAGA?CCAGCCTGAT?CAACATGGTG?AAACCCCGTC?TCTACTAAAA?40200

ACATAAAAAT?TAGCCGGGCA?TGGTGGCAGA?TGCCTGTAAT?CCCAGCTACT?TGAGAGGCTG?40260

AGGCAGGAGA?ATTGCTTGAA?TCCAGGAGGC?AGAGGTTGCA?GTGAGCCGAG?ACTGCACCAT?40320

TGCACTCCAG?CCCGGGTGAC?AGAGTGAGAC?TCTGTCTCAA?AAAAAAAAAA?AAAAAAAGTT?40380

TTCATTCCTC?AAGATAAAGA?AGAGATGGTG?GCAATAAGGG?GAGAAATGGA?ATATAAAATG?40440

TTGCTCCTAA?TGTCTGCTGT?TTTAGGTGGA?AGAAATATCC?CACCACACAG?AAAAGAGATG?40500

CTTAAAAAGC?AAACACCCCC?TACCTTCTGG?AGCATTTTAG?AAGACTCTGA?AATCACCCAG?40560

ACATTTGAGT?CGTCAGCTGT?GAAAGGCTTC?CTGTACTGTA?CAGTGAGAAA?TTGTCTTTAT?40620

GCTTATTATC?TCACTTCATA?AGAAAGTCTG?AGAATAAATA?AGAGGAAAAA?TATGAGGGAT?40680

GCCCATGATG?ATCACTTGAG?TTGAAAGACT?CTGAAAATGG?AAGTCATTAG?TATCTGAAAG?40740

GCTCATAGTA?AAATATAAAA?TGCATGATAT?ATTTTGACAA?AGATATTCAA?TGATAAAATA?40800

TAGATCCAAC?TTGCAGGCCA?TTTATCAACT?TTTGTCCTTT?TGGAGGAAAT?AAACTTGTCT?40860

ACTGTAGACA?AGCTGGTATA?CAGAAGGAGA?GAAAAGTTTC?TTCAATGCTA?GTAAACATGC?40920

CTGGGTATTC?TACTGTCAGA?GATTAATTCC?TTTGGCTTAG?CCTAGGCCTT?CTTTTAAAAG?40980

GTGATCTACT?TGAAGAAAGC?TGACCTGGTA?AGTCAGAATA?TCAGGTGTTA?CCATGTTTCA?41040

TGTGATTAAA?CTATTTAGAT?TTCCCTCCTA?ACTCAAATCA?CATAAAGAAC?ATGAGGCCAA?41100

GCACAGTGGT?TCATGCCTGT?AATTCTAGCA?CTTTGGGAGG?CCAAGGCAGG?TTATTCACCT?41160

GAGGTCAGGA?GTTCGAGACC?AGACTGACGA?ACATGGTGAA?ACTCGTCTCT?ACTAAAAATA?41220

CAAAGATTAG?CTGGGTATGG?TGGCACACTC?CTGCAGTCCC?ACCTACTCAG?GAGGCTGAGG?41280

CAGGAGGATC?ACTTGAACCT?GGGAGGCAGA?GGTTGCAGTG?AGCCAAGATC?GTGCCATTGC?41340

ACTCCAGCCT?GGGCGACAGA?GTGAGACTCC?GTCAAAAAAA?AAAAAAAAAA?AAAAACAACC?41400

AGAAAAGAAA?ACGAGAGAAA?TGGACCATTT?ACAGGATGAG?GATGAGAACA?TAGGAAGGAA?41460

GAGTAATCTG?GAAAGCGTTG?CCCTGACAAG?ATGTGCATGC?CTGCCTTCAG?TTCACTGAGA?41520

AGTTGGCCTG?GGGGATGTTG?GACAGGAAGA?TAGGGAGAAT?GGCAGTAGGT?GAAGGACACA?41580

GGAAGAGAAC?AAGCTGGATC?TGCAGTGCTA?CTGAGCACCA?AACACGAAAC?ACGAGGACAC?41640

ATAGCTTCTC?GCAGGTGGAA?TGCACATGGC?CGCAGAGATA?GGGTGTAGAG?CCAGCATTTG?41700

TATTTCAAAA?AGATTTTTTA?ATTAAATCAG?ACCTATTGTT?GACTAAACTA?ACATTTACAC?41760

TACCACGCTG?GTAAAATTAA?AAGACTTATC?CATTCCCAGT?GTTGGAGAAG?GTACACGGAA?41820

ATCCATATGC?TTACATCCTT?TTCAGGAGGA?GAATAGTTTA?GTAGTGCTTA?TTCAAATTTA?41880

AAATACACAT?ATTTCTAATC?TAGAAATTTC?ACTTCTGGCA?ATCTGCCTTG?CAGAAATATT?41940

AGCACAAATG?CATGAGATAT?TTTTACAAAG?ATATTCAATG?TAGCATTAAG?TGGAAAAACT?42000

GAAGACAATC?CATCAACAGG?GACATGATAA?GATCCATCGT?GGGAGATAAT?ATGAAATTCG?42060

AGACTAAATT?AAAAGATGTA?CAGTATATCT?ATGTGTTCTA?TCTTGTTTAG?AAGGAATTGT?42120

AAAAGTGGTT?GGGTATAAAA?AAGTGTTGCA?AAATAATATT?TATAGTATGA?TCAGATAGTT?42128

GTACTGAAAG?ATGGATGAGT?GGATGGAAGG?ATGGACAGAT?GGATGAAAGG?AGGGAAAGAG?42240

AAAGGAAGAC?AGGGAGAGAT?TGGGAGAGAG?GATGGAGTGG?GAGATAATAT?GAATGAATGA?42300

TAGAGACGTG?TGTGCATCTA?ATACATTGTC?AATACAGATG?ATCTGTTGCA?TTGGGAGTGA?42360

GGGGAGGACG?AAAATGTACT?TTCATTTTTA?ATTTTCACAC?ACTGTTGGAT?TGTTTGAAAT?42420

TTTTGATGAC?GAGCATATAC?TACTTTTGTA?ATTAAAAACC?ACTGAATTCT?CTTCTTATTA?42480

AAAATTGAGG?GAATAGTGTA?TGCCTTCCTT?TCAAGCTGAG?TAAACGCTGA?ACTTCAAAGA?42540

TGGAGGCTAG?TATCTAATCT?ACTCTTCTCC?TGGCTCTAGG?GGTAAACTTT?GGCTTATTAT?42600

TTCCTCTCTG?TATTGCAATG?TTTCTCTCAA?ATGGGATCGA?TGACAAGTAC?CCTAAAGACA?42660

AATCCTGGGA?CTATGTACAA?GAAACAACAT?CAGTTATAAA?GAAAGTCCTC?CTCCAAGATT?42720

AAACAACCCC?ATCCAAATCT?TTAGAACAAT?AGTTACCAAA?TTTTAGCTGC?ACAGAATTAC?42780

TGGGAGGGCT?TGTTAAAATA?CAGATAGCTG?GGGTTCACCC?TCTATGTTTC?TCATTTAGTG?42840

GGGCCTGAGA?ATCTGCATTT?ATAACAGGTT?CCCAGGTGAT?ACTGATGCTG?GCTGCTCAAG?42900

GGGCCGCACT?TTGAGAAACA?CTGCTCTAGG?TGAAAGAAAC?TATTTGTCAA?AGACAAATAA?42960

TAATGTTTGC?CCCAGTCAAC?CATATTTGAT?GAGAACCAGA?ACAAACCCTG?CTACTCCCCA?43020

AGCCCCTCTT?TCCACCAGCT?GAATGAGCTC?CTAATCCACT?GTATGCAATC?CACCACAGGA?43080

GGAATGTGCT?CTATGACACT?GCAGACCAAG?GATACAAAAA?ATTGGCACAG?ATCTCAGGTC?43140

CCACACCCTT?AAGAGAAGAA?AACTCACCTT?CTGAGAAGAT?GATGTTGTCA?TTGCACTCAT?43200

CAGAGCTACA?GGAACACATG?AAGAAAGTCT?CACCAGGCTT?TTTTTTTTCC?TTCATAATGC?43260

ACTTTGGAGA?AGCAGCATCT?TCCAGAATAA?AGTCATGGTA?GGGGAGCTTG?GGGTCATGGC?43320

AAACTGTCTC?TAGTGTTATG?TTCTCGTCAT?TCTTTCTCCT?AGAGTGAAGA?GATTCATTGG?43380

AAGCGAGGGG?AGAGGGAGAG?AGAGAAAGAG?AATAAATGAA?TAATATGGCC?TCCAGACAGA?43440

AAGGCAATCT?GGAATACTTT?TCCTTCATGA?AGTTGTTCCT?AACAACGGCA?GCTGGTTCCT?43500

GTTCTCCAGC?ATTCGCAGGC?TGTCCTATAG?TCTCCTATGC?TTTTCTACTC?TTTTCTGTTT?43560

TTCCTTTGTT?TATTCTTGGA?ACCCATTTGT?GATTATAAAC?ATCACCTGGA?GCAGACAGCG?43620

TTCCACGGGG?CAGTCCTGGT?GGAGAATTTT?ACATATTTAA?GTCTTAATTA?AATCATTAAA?43680

GGGGAAGACA?TGGAAAAAAA?GAACATTCCT?AGGTACTCAG?GATAATTTTA?AATCTTCCAT?43740

CCTGAATGTA?ATGCAAACCT?CACATCACAC?CCCTAGTTTA?ACTGGCAAAA?TCTGTCCTGT?43800

CTAGCTATAC?TGTTTTCAAA?GAGCATGCCT?GGGGAAATAG?TCACAGTTCC?TCTTTTTTTT?43860

GTTTGCTGGG?CCCCAGAGCA?TTGCGTGTAA?AGGGTATACT?CCTTGTCAAC?AGCTGGTTCT?43920

GCTGAGAAAA?ACGGGAAGAA?ACATCGCAGA?TAAAGAACTG?CAGTCTTTCC?CAAATTACAG?43980

AAAGGAGCAA?TTCAGAAAAA?ACAAACAAAC?AAAAAAAACA?AATAAATAAA?AGAAATGGAA?44040

AAGGATGTCA?GGGTGTTCTT?CATTTACAGT?TCAATGAAAT?ATTTTATGCT?GTCATAAACT?44100

AACTACTTTG?ACAGTATCAC?TTCATAGCAC?ATATTTGAAG?ACTAATTTAG?CCCAGGGCTC?44160

AGAGAATTTC?TCACATAGCA?TTTTCCTTGG?GCCCTAGGAA?ATGCTCAATT?GGCCGTCAGT?44220

GTACATTAGA?TTTTTAAACA?ACATGATTAA?TGCCCACTAT?TATAATTGAA?CAAAAGAACA?44280

TTTTGGCTCT?CTTGGAAAAG?GGTATCACCT?CTCTATCTAC?CTCCCTCTGC?TCCCTCATGA?44340

ACATACTATC?TTGGATGACT?GTCCAACAAG?GCTAGTCTGA?CATCCACCCT?TTCACCTCTG?44400

TCCTTTTTAG?ATGCAAAATA?CCTGTTGTCT?TGAATCGCAT?TCTCTCTGTC?TAGAGAGGGA?44460

GCGGAAGGAA?GGGCTAATCT?GGTCCAGTCA?GTTTTGCTAG?AGTAATCTTC?TATGAAGATT?44520

CTGAGTGCAC?ACATGAGCCA?ATGCATGCAT?GTACTCACTC?ACCAATTTTC?CCCTAATCCT?44580

CCCTGCCCCA?TGCACAAAGG?CTCACTGCTC?ACAGCAAGGA?AAACGGAAGG?CAGGCTAGAA?44640

GCAAGAAGCA?GCTAAGACAC?AGCTTGCACC?TATAAAAGAT?GCGGGGCCAT?CCCCACGAGA?44700

GAAAGAGCAA?CTTTGACCAA?TACCACTTTT?TTAGTGCTTA?AGTCAAGGAC?ATTAAAGGAC?44760

AATATGTTGA?CAAAGGGATA?AGGGCAAGGG?TATGGGTTAG?GACAATCCAG?GCAGGAATGG?44820

TGCCAGTGTC?AACATCCATG?CAGCCCAGAG?TTGACTCCAG?TGGAGGTACA?TGTGTCTGCT?44880

TGTGAAGGGG?CTCAAGGGTT?CTTAAACTAG?AATTCCGAAA?GACACAAGAG?GAGCAAGGCT?44940

TTGCTAAGTT?GGTCCCTGCT?GTGACAGGAA?GAGTGACAAG?CAGAATAATT?GGTTGAGGGT?45000

GGCTATCAGG?ACACCAAATG?AAACTAAATG?AAAGTTGGCA?TGATCATACA?ACAAATGATG?45060

TATAATTTGG?AAATCTACCC?ATCTTTAACC?CCAAAGCTAC?TTGGCAGTCT?TCAAATCAGC?45120

TGTAGTCATG?GAACAAGAAC?ACCTTCCTCC?CTGCCCCCAC?AGTTTTGTGT?GTGTGTGTGT?45180

GTGTGTGTGT?GTGTGTGTGT?GTGTGTGTAG?GTTGTTTTTG?GTTTGGGTAA?TAAAACGAAG?45240

GTATGCTGTG?CCCACAGAAA?GGCATGGTCT?CTTTTCCTTG?TGACGCTTAT?AGAGGCCTAA?45300

GAAGGAACTG?TGAGCCATGA?AAGAAAGCTG?CTCTATAATT?ATTGGGCAGC?TCTTCCAGAG?45360

CCTCCGGTTT?TCTACCTCTT?AGCTACTGAG?AGAACTAACA?TCACAGAGAG?AAAACAACTG?45420

TAATACTTGA?GACCTGGTAA?AGCCCTTAAC?TGCTTTCTCC?ACTCACTCCT?GTAACAGCCA?45480

GGCACAGCTA?ACTTTTCAAA?CTCTTTTTGG?ATATAGCTGA?GCATAGGAAA?GGTAAATACA?45540

AAGAAGTAAA?TACGGACTTC?TTTTTTTGTC?CTGCAACATT?TGCTCTGAGC?CACTGAAGAG?45600

GTTGTCAATT?TCCACTGAAA?GAAGAACCAA?CATGATAAAA?TTAATTTTGG?AGGCTGGGCA?45660

CGGTGGCTCA?TGCCTGTAAT?CTAAGCACTT?TCAGAGGCCG?AGGCAGGCGG?ATCACAAGGT?45720

CAGGAGTTCG?AGACCAGCCT?GGCCAACACA?GTGAAACCCC?ATCTCTACTA?AAAATACAAA?45780

AAATTAGCCA?CGTGATGGTG?GTGTGCACCT?GTAATCACAG?CTACTCAGGA?AGCTGAAGCA?45840

GGAGAATCGC?ACGAACCCGG?GAGGCAGAGG?TTGCAGTGAG?CCCAGATCAC?GCCATTGCAC?45900

TCCAGCCTGG?GCAACAGTGG?GAGACTCCCT?CTCAATTTAA?AAATAATAAT?AATAATAATT?45960

TTGGTTATAA?AATATTTCTA?TCCTTGGAGG?CAGCTTAAGC?ATTTTATATG?GAATGGGCAC?46020

ACAACTGACA?TTAGTTAAAT?GAATGAATGA?ATGAATGAAT?GAATGAAAAA?ACACTAAAAC?46080

TGATTAAAAA?AACAACAACA?CTGAAATCTA?CAATCATAGT?AGAGCCTTTC?AGTTTCCACA?46140

CTGGCTATTT?TTACAATAGC?CTCCTGTCTT?AGTTTAGGTT?TCCTGGAAAC?AGACCTTGAG?46200

GCTGTGAGAG?TTCTGTGCAG?GAGGTTTTTG?GAGATGCATC?TGTAAGCGAC?TAAAGGCAAC?46260

AGTATTGCAC?AGAAGGAAAA?AGCTAAACTA?TAATGCAGGT?TGCAGCAAAG?GCCTCAGTGA?46320

ATGCCTTGGA?AACTCTGAAA?ATGGGATGTC?CTTCAAAGAT?GTACCACATT?ATGGCAAAAT?46380

AACCAGGAAT?TTGTTTCTCT?GCATCAACTA?GCCATGGGAT?GATGGCTACC?CATGAAAAGT?46440

GTCCAACGTG?AATGAGGCAG?CTCCCATCAC?TGGAGGGAAG?GCTCAGCAGT?GATCCTTCAA?46500

CAGCCAACAC?TCCCAGGGAA?TGAGTGCCTT?GGTCATGAAG?GAGGATCAAG?GAGGGCACTA?46560

TAGCGTACCC?TATACTTCCC?CTTCTCATTA?TCAACACCCC?TGGCTTCACG?GGAGAATTTT?46620

CTTTGGCCAG?CACAGGTCAA?AATAATGTTC?ATTGTATTTA?CCCTTTATAG?CTGGGACACA?46680

GAAAAGACAG?GGAGGCCTCC?TCTCTTCGAC?ATGCTCACAT?TTTTTTGAGG?CTAGCAAAGC?46740

CTCTATTCTA?GAGAGACTTG?ATTCACATTT?AATGATTTGG?GCTTGTATTA?CTGGTCAGGA?46800

AAACAAAAAT?CTTAATTAAA?AGAGCCTTTT?TGGGTTGCAA?AAGCAAGTGC?TCACACCACC?46860

GTAGATATTT?AAGAAACCAC?GGAAGGAAGC?TTTGAGGCCA?TCTAGTCTGG?TGTCTCAATC?46920

TTTCCTGCAT?TCTATTTGAC?ATATGGTCAT?CCAGCCTCTC?CTGAACTTCA?CTTGGTGCTT?46980

ACAGAAAAGG?AAGCCTGTTC?TGCTGTTGGG?AAACCATGAT?TGTGAAAATG?TCTAAACTTA?47040

TGCTGAGCAC?AAGTCTGCCT?GCCTTGCAAA?TGTTATGGAT?CCTCCCTCTA?CCCTTCAGAG?47100

TTATGCAGAA?TATGTTTATT?ATATTTTCTA?CCTGAGAGCC?TTTCAATTTC?ATCAGCAGAA?47160

CCCACGATCT?CTCTTCACTG?TACTAACCAT?GTCTAATTGC?CCAGGCCATT?CCTCAGACAG?47220

CATGATTTCT?AGGCCTCTAA?CCACACTGGT?CCCTCTCCTC?TGAACACATT?CTTTGTCCAA?47280

ATCCTTTCTT?TGAAAGCGTT?ACCTAGAAGT?GGACATGGAC?AGGTATCATA?TCATATTGGC?47340

AAGTATGTCA?TGACAAGTCT?TTGCTGTTAA?CATTCCTTCA?GTTCTTAAGA?AACCAGTTCA?47400

TCCCGTGGTA?TGTACAGAAG?TTTGCAAGGT?TTCCAGATCT?ATCATCAAGG?CTAGCTTTAC?47460

ATGGTCTAGG?GGTCTCAAAT?GACTCATTCC?CAAAAAAGGG?GGAGAGATAT?TTGGGTTTAT?47520

ATTCTTGTTT?GTCAACTAGC?CAGGAGACAC?ATAAGTTACT?TTTTTTAAAA?TGGCCAATAA?47580

ATTAAAAACA?TCAGAATAAG?TCTGCAAAAT?GTCATATCTC?ATTAATGAAT?TTATGTACTT?47640

TTGTAAAATT?ACAACTCTTC?TAAAGATCAA?GGTTATTTCT?TGTTCATGCT?CACAATCTAT?47700

AACCATGAAT?TAATCAAATG?ATTCATGAGT?ATCCACTGTG?TATGTATAAT?TATTATTTGA?47760

GATGTATGTA?TGAGTTGGAG?GGAATGAGAG?AGAGAGAGAG?AGAGAGAGGA?GAAAATGTGA?47820

TCCGATAAAA?ATATATAGTT?CTGGTCGGGC?ATGGTGGCTC?ATGCCTGTAA?TTCCAGCACT?47880

TTGGGAGGCA?GAGGCGAGTG?GATCACCTGA?GGTCGGGAGT?TCGAGACCAG?CCTGGCCAAC?47940

ATGGTGAAAC?CCCGTCTCTA?CTAAAAATAC?AAAACTTAGC?CAGGTGTGGT?AGTGGGCACC?48000

TGTAATCCCA?GCTACTCGAA?AGGCTGAGAC?AAGAGAAACG?CTTGAACCTG?GGAGGTGGAG?48060

GTTGCGGTGA?GCCAAGATTG?TGCCATGGCA?CTCTAGCCTG?AATGACAGAG?CAAGACTCCA?48120

TCTCAAAAAA?AAAAAAGAAA?TATGTAGTTC?TGAGCTGAGA?GAAAGAAGTC?ATATCTATCC?48180

CAATGGTTAT?ATGAATAATA?TAACCAGAAT?TTCTGACTAA?AAAAACAGGT?TGTTTTTGTG?48240

GTTCTCCAAG?TAGATTCCCC?ATTTTTGGCT?GGTAGTTTTC?TCTTCCAACA?GCCAACCTTT?48300

CATCACCTCT?TCTTCCAGAC?CTGAGATTGC?CTCAAGAGAA?CAAAGCTCCT?GGTCTCACTA?48360

TGGGGTGCTG?AGGAGGTGTC?GGTTAAATGA?CTACTAAGCG?GCAAATCCCT?CTTCTTGATA?48420

CAAGAAAGAG?TTTCCAGATT?TATTATATTA?AAGATCATTT?TATGATCTTT?ACATTTATCA?48480

TGATCATTTT?ATAATCATGA?TACGTTTATA?TACCCACATA?AACGTACACA?TACATGCAGA?48540

GAACACCCCT?AGAAACTACA?TTTAATAATC?GAAAGAGAGA?TGGTCTAAAG?GAAAGGGAAA?48600

TGGAACAGGT?GTTTACATTT?AGGAGACAGA?GATACACTGA?CTGTGTGTAC?TATGAGAATA?48660

CATTATGTAA?AAAGGGGAAA?AGAAAGAATA?ACTTCTTAAA?AGGCTTGCTT?ACCATACAGC?48720

CACACAGACT?TCCTGTGGCT?TCTCACAGAT?GGAGGTGATG?CTGCAGTTGC?TCATGCAGGA?48780

TTTCTGGTTG?TCACAGGTGG?AAAATCTCAC?ATCACAAAAT?TTACACAGTT?GTGGAAACTT?48840

GACTGCACCG?TTGTTGTCAG?TGACTATCAT?GTCGTTATTA?ACTGAGGAGA?GAGAAAGATA?48900

TATTAAATGA?TTATCCAACT?GCCAGGCAGC?CTGCCAATGA?ATTCCTGAAG?ATGTTATGCA?48960

ATTTCAAATG?AACTTGATGT?CATGAGAATG?AATCTGAAGA?AAGGCAAAAT?AATTCCTTCA?49020

CATCAGATTA?GAATTATCTG?GTGTATGCAA?TTTGTAATAA?AATCCATTGT?ACCGTGGTGA?49080

GGGGTGGTGA?GGGGTTGGGG?TGGTTGAGTA?GCCATTTGCT?TTTGTCAATG?GTTGTCATAA?49140

GGTCCACTTT?CTACAAAAAT?CTTATCATTC?AATAAAGAAA?CCTAGATGGG?CCCACTGCAT?49200

AGTACGGAGT?GCTGGGCCCA?CAAATAAAAG?TACCCTTAAG?GAAATTATAG?TTTAGCTGGT?49260

GAATAAGACA?GGAAACAGAC?CAAGTCAGGG?TGACCCAAAA?TAGAGGGCAG?CACAGAGGAT?49320

GTGGGAGCCA?GGCGAGCATC?ACCGCTCAGC?TGGGCAGGGA?GGCTATAACC?TCACAGAGTC?49380

ATGAAGTGCC?ACACCAAAGG?AGGAACCGTT?GCTGGAGGCA?CAAGATTTTG?CCGCCATTTT?49440

CCTGACCTAC?TCCTGAAAGA?GCTATAAGGG?TCTTCTTTTC?AAGGGACTAG?TTCTACTGAT?49500

CTCTCTCTGT?GTTTGAGGCA?AATCAATTGA?TTAACTAACA?CTTACTGAGT?GCCTCCTAGA?49560

CACAATCCCA?AGCATTGGTG?AGGCATTGGA?GTTATGATCG?CAGCAAATAA?AAGCTGAATC?49620

CACCTCAGGA?TCTGCCTTCT?GTACCTCTCC?CTTATCACCA?CCATCACCAA?TCTCCTGCCC?49680

CCTTCTGGGA?AGAAGCCAAG?TTCATTCCCT?CCTCAGGCCT?TTCACTTGCT?ATTACCTTTG?49740

TTTAGCTTCC?TGTCACTTTT?CTGATCTCTG?ATCAAATGCC?ACCTCTTCAT?CCTATAGCAA?49800

CTCTGTTTTA?TTTATTGTCT?GCACAAACTA?TCTGCATCGC?ATACTTGCTA?ATAATCTATC?49860

CACAAAAATG?TAAGCTCCAT?GAAACTTTCT?CCACCTCACT?TACCTACTAT?ATCTCCAGTG?49920

CCAGGAAGAG?AACCTTTCAC?ATAGCAGGCA?TACAAAAATG?TTTATTGGAT?AAATGAGTGA?49980

ACACAGGATG?AATACAAGGA?GTCCATGTTT?GGCCCTTGAT?GCCATGTAGG?ATAGGATACA?50040

GAACTTCTTC?ACTCAGATTA?GAGAGGAATG?TGATTATAAA?TGTGATATTC?ATTCACATTT?50100

ATTCAATAAA?ATATGGAAGA?CAGACTATTC?TTTGCAAAAT?ACAGGCTGCA?AACTAGGGGC?50160

AGTTCAAATA?AAGGTGTAAC?ACCCCATTCC?CCATTTTCTT?CCTCAATGAG?ATGGTGATGA?50220

TGTTTAAGAC?ATGAGTTTGG?ACAGTCAGTG?AAGTATGACA?AGGCTACTAG?GCACTCAACC?50280

AGCAAACATG?AATTAATACT?TACATGCTAG?ACTAAGAAAC?ATTAAGCACT?TAGACCGCAT?50340

GGGGTGCTGG?AACAGTTGCT?GGGCCACAGA?AAGTTGTGAG?GTACTTTTCC?AAGGCATAAC?50400

CCTTAGAGAG?GCCTAAGAAA?AGCCTCATGT?TCCCTCTGCT?CTTGCCTAGA?GAGGAACACT?50460

TTCAATGCCT?TTCCACAGTC?ACTCTCTGTC?CTGTGAATTT?TAGGATTCTG?TCATAGATAC?50520

TTTGCCCTGC?AACTGTCTTT?GTAGCTTGGG?CATAGCACCT?GTTTCCTGGG?TCTCTAAAAA?50580

TATAAACGTA?TATAAATTTA?AGATTTGCTT?TCTTGTGGTA?ACAGTAAATA?TAGAAGAAAA?50640

AAATAAAGCC?ATTCATCCCT?CTCGGGCCTC?AAGTTCATTT?CAGGAAGTTT?ATTTTTAGGT?50700

AACAAGCTAT?TTTGAAATTC?TCAGTGTCTC?CCAGACCAAG?AGCTCTATGC?TTAGCTAAAA?50760

ATATAGGCAG?AAATACTCTC?TGAACTGTGT?GAAATTTGGG?AGAAACACAA?CAATTAATAT?50820

GTATTTTTTT?CTAACATGGT?TATACTTGGA?TCAATTTTTG?AAACAACTAA?TAACACTTTA?50880

GGTTTCTTTA?ACATTGTTTA?AAGCAAAAAA?AAAGTGAAAC?CACGTTTTGT?TTATTTCATA?50940

CATACGTATT?TTTTGTATAG?AGTATGTTTT?GGACAAGCAT?CTATTTGCTG?ATTAGGAAGG?51000

TTTGTTGTTT?GTAAATATAA?AACCAAATTT?CCATTACTTG?AAATTCAGTC?TTCCAACATC?51060

TTAGGATTTT?AGCTTAGATT?GGTGGTTATC?AACTTGGAGA?GCATGTTGAA?ATCCATCACC?51120

TGAGGAAATT?TAAAAAATAC?TGAAGGGGTC?CCACTCCCAG?ATAGTCTGAT?TTAATTTTTC?51180

TGGAAGGTAA?CTGAGGCATC?AGGATTTTTA?GAAGCTGCCC?AGATGATTCT?AATGTGGAAC?51240

CAAGGTTGAG?AACCCAGACC?TATAGTTAGT?TGGAAAAAAC?ACAATAAACA?GAAAACAAAA?51300

CAGCAACCCC?CCCACTCCCA?CCCCACCACC?ACAAACACAT?ATACAACTTA?TGCTGCTGAG?51360

GGGACAGCAC?CTGGATATAG?CTGGAATTAG?TTCCCTTGTG?AAAAACATGC?ACCTAAGGAG?51420

AGGTGATTAG?CTCTTTCACA?CCTCAGATAG?AAATTCTTCT?CCGTGCTGGC?CAGTCCTTTT?51480

CTAGCAAAAC?CTTAGAAACG?TGAGAATAGT?GACAGGAGTG?AGCAGCGATA?GATAAGACAG?51540

AAATGAAAAC?AGATGAGATG?GGTGCTGGGA?GCAGTGGTGG?CCACAGATGT?ATTGACAAAT?51600

GCAAGTGGTT?TAAGTCCGAT?GCTTGCAGAA?CACAATCAAC?AGGGAAAAGA?AAAAAGGACC?51660

ATTAGAAGAA?AGAAAGGGAG?AGAAAGGGAA?GAAGGATGTA?GGGAGAGAGA?GAGGAAGGAA?51720

GGGAGGAAGG?GAAACAAGGA?GGGAGGGGGA?GGAGAGAGAA?AGAGAGAGAA?GGTCCACCAA?51780

TTTGCACAGC?TCCAGGAGCA?CCACTGTAAC?GGGGCCCCTG?GCGAGATATA?ATACATGTTA?51840

CTTGATGGGT?AGACCCAACA?AGAGAAAGCC?TTTCCATTGA?ATGTTGAAGA?AAAGCCAAAC?51900

AAGCAACTGT?ACTGCATATA?GACACAGGCA?TATGGTGGGA?AGGGCAGTGT?ACAATAAGAA?51960

TTTGCACATG?CTGAGCACCC?ACTGTATATG?AGGAAAGTTG?CCTAAGATAC?AGCATATTAC?52020

TTCACAAGAA?CCCAGCCAGG?GATGCCACAT?TTTTCTCCTT?GTTACAGCAG?AAGCTACCAC?52080

TGCAAGAGCT?TAACCAGAAT?TTTTTTTCAA?AAGCCTGTAT?GCAGGACATG?TTCAGCACCA?52140

GCCATCGACT?CCCTATTAGT?TGACCCTAGG?AGACTCCCCA?CCTTAACAAT?TCCAGGTAGC?52200

CCTTGAGGTC?ATATACATTC?CAACCTTTGT?TTTAAACCAG?TATTCTTTTC?CTCTATATGA?52260

TATAGGTCCT?CAGGTCCTTT?TATGCATACC?ATATGTACTG?GTGGAATAGG?TAGTTAAGTT?52320

CAGAGGGCAA?AGCTACTCTA?AACCTTTGCT?GGAGTCACCT?AAGTTTGATA?AAAGCCTTAT?52380

GAACACACTT?TGGAGTTGGG?GAAAAGAAAC?AAATACAAAA?TTTGTAGATC?ATCTGAGAAG?52440

GTTTGCAGAT?TCTCTGAGGC?CCGTAAGATC?CAGTTAAGGC?ATCCCAAGCC?AACCCCGGAA?52500

TCCTCAAGAG?TCACTAATAA?CATGCTAAGT?GGTATACTGC?TGGTCAGAGT?GGGATGAGGG?52560

CCAGTGGGAG?GGAAGGGTAA?CAGTCATTTG?CTGTATGGGA?CATTGCATCT?GTGCACTCCA?52620

AACCACAGGA?AAAGATGTTA?CCAGCCACGA?CCTCAGATAT?CAAACAACAT?CTCCTTACGT?52680

TTAATACATA?ATGTTTAAAA?AGCCAAAGGA?ATGGGAAGGA?AAGTAAGTGC?ATACATGTGC?52740

ATAGCTAGGA?ATAAAGATAT?TCCTCTAAAC?AACGATACAA?AACCCACCTA?ATTAACCCTA?52800

TAGCAAACCC?TAACCCAACT?TCAACATTAC?TTTTAATCCA?GATTGTTATA?TTAGTCTAAG?52860

TCTCTCTAGT?TAAGATATTC?TTATATTAAG?GCAGTATATA?GTCAGCCTTC?TGTATCTGTG?52920

GGTTCCACAT?CTGCGGTTTC?CATCAACCGT?GGATGCAAAA?TATTTTTTTA?AAAAAATTGA?52980

TGATTGTGGC?TGTACTGAAT?TATGTACAGA?CTTTTTTCTT?GTCATTATTC?CCTAAGCAAC?53040

ACAGTATAAC?AACTATTTAC?ATAGAATTTA?CATTGTATTA?TGTATAAGTA?ATCTAGAGAT?53100

GATTTAAAGG?ATATGGGAGG?ATGTGTGTAG?GTTATATGTA?AATATTACAC?AATTTTATAT?53160

AAGGGAGTTA?AACATCTGTA?GATTTTGGTC?TCCTCGAGGA?GTCTTGGAAC?CAATCCCCCA?53220

TGGGTACCAA?GAGATGACTG?TACTTCGATT?CCTATAGACT?CTCTGTGAGC?AGCTAACCAT?53280

CTTTAGAGAA?TTTTCTACCC?CTAATAGGCA?AATTCGTTAT?TCATAAAGTT?CTCCAGAAAG?53340

AAGTTCCAAT?AAGAATATCT?GTCACCTAGA?AAGCCATCCA?CTAAAGGAAG?TGAACATGGG?53400

TAGCATCTCT?CAGCATATGA?TAGTATCACA?TGGCCCATAA?TATTTCACTT?CTCTTCAAAT?53460

AAGCCCATGA?GTAATATCAA?AACCTTCACT?CTAGGTCATA?CCACCTTCCC?CATTTTATCT?53520

CACATTTTCC?CCACACTCAC?TGCCTACAGA?CAGAGGTTCC?AGGTCTTGAG?AATATGAATT?53580

GACTGCTTAG?CTGTGTCTAT?TTCTGGAACT?GTACTATTGT?CTTTGAGGGT?CAGATGAGCA?53640

GCCTAATAAG?ATTTAGACTT?ATTTCAGATA?AATATTAGAA?ATTCTGAATA?TGACCTTAGT?53700

CCAAATCTTT?GAAATAGTGT?CTATTATTAG?CTGAACCATT?AGGTAAAATC?TCAAGGTTTA?53760

ACAATAACCA?TAAACACTTG?TCAGAAATGC?ATTCATGTAT?CACTGAATTC?ATGCATTCGT?53820

GTATCATTGA?ATTCATGTAT?CTACCGACTG?TTGTTTTCTG?GAGTGTTTTT?TGTGGGGGGA?53880

AACTCAGAAA?TTTATTTGTT?CTACAAATAC?CTGTGGATGT?CTTGATTAGT?GTTATATATT?53940

CATAGTAAGA?CCACTGAAAT?TGACACAATT?AAATAACATC?TCAAAGAATA?ATCCATGGAA?54000

ACTGGTGGAT?AGAATTTACT?GTTTTAGAGT?ACTGCTTCTC?AAATATTAAT?ACACAAGTAC?54060

TTTGGGAATA?TTTTTAACCT?GCAGGTGTAG?CATAGTGGTA?TTGTGGGGGC?TGGCAAGTCT?54120

GAAATTTATA?GGGCAGACTG?GCAGCCTGGG?AACTCAGGCA?GAAATCAATG?CTGCAGTTTT?54180

GAGGCAGTAT?TTTTTCTCTC?AGAAACCTCA?GCTTTTGCTC?TTAAGGCTGT?TCAGTTGATT?54240

GGATGAGGCC?CACTCACATT?ATAGAGAATG?ATTTCTTTTA?CTTAAAGTCA?AATGATTTTA?54300

GCTGTTAATC?ACATCTACAA?CATACCTTCA?CAGCAACAAT?GAGATTAGTG?GGCACCAGAA?54360

CCTAGCCAAG?TACACACGAA?ACTGACCTTA?CAGATAGGAA?GGGAGCTGCT?GCCCTGGGTG?54420

ATGCCAGCCC?ACTATATGTT?GAGTGGGAAG?GCTGTGGAGA?ACCCAGTTTT?TAATAATTGT?54480

TTCCCTTTCT?CCAGTCATTT?TGGAGTTAGT?GAAATTAAAT?ACCTATTCTT?CACCTTTTTA?54540

CAGGCATTTC?TCATCTTCCA?GTTCTTTCCA?TATGCTTTTC?TCTTGAGCCT?GACCTCTTAA?54600

ATGATTGCAA?ACCCAGAGGC?CCTGATCACC?ATATGGGCCC?AGAATTGAAA?GACATGTTCT?54660

CTGAAAGGAG?GTTTTTAATT?GCCTGCAGCA?TTTCCGAGTC?AGATACTGAG?GCAGCCATCT?54720

GGCAGAAAGC?CGCTGTGGCC?TGTGATGCTA?GCAACAGCAG?CTCCGACCCT?TGAGACAAGG?54780

TGGGACAAGG?CTATTGGCTA?GTCACACACT?TCCTCCCACC?CAGAACAAAG?AAGAAAGTCA?54840

AGCAATCTGA?GAGGATTCCC?TGTATAATTC?TTCAGGAAAG?ACATCCCCAA?GCCAATCAGA?54900

TACCTTGGCC?AATTACTACA?ACCAACCAAC?CAACCAAACA?AACACCTTGT?GATTAAACCA?54960

AAGATAGGAA?CATTTTAGGA?ATAGTTCTTT?TTGCTGAACA?TCTATTGCAC?ACTCTAATTG?55020

GAACTTCTAA?TACAATACCT?TCTTTTTAGT?TTTTAAAAAT?GTGTTTGAAC?CCTAATGCTT?55080

TATCTAATTA?TACCTTGAGA?GAAGAGAGGT?ATCGGGCTTT?CCTTCAACTG?ACAGTCCACA?55140

TGGTCTCTGG?GGTACCAAGG?TCAATACTAG?AGATACCATC?ATTTAGCTAA?CAGGGAGACT?55200

ATGGCGTGTG?CAGGAAGAAA?ACAGAGACAA?GTGACCTGAA?GGCATCAATT?CTCCTTCTTA?55260

TGCAAATATT?TTTGTAGTAA?TAATACTTTA?AAACCTTTCA?GAGATGACAA?AGTGAATACT?55320

CTAAAATCTC?TGTGAAATGA?CAATGCCTTA?TAATTCTTGC?TTTTAAATAG?TAAGTATTCT?55380

ACAAGTGCCA?GAAGAATTAA?TGCCATTTAA?AATCATTATC?AATGCTTATT?GGAAACAAAT?55440

AACAAATCAT?ATGAGTTCTC?TATATTGTGT?TAAAAAAACG?CTACTTTAAA?TATTACTTCC?55500

TGATCATATC?ACCAGAGAAT?AAGCTCTAAA?AGCGAAGCAT?GTCAACCTCA?TTGCTAACAA?55560

GTGAAATGCA?GATTAAAAAT?GCATACCATA?TTTCACCTAA?CTCATTTTGA?AAAAGATCAA?55620

TAAGTCAGAT?AACACAGTGA?GCTGGGTAAA?GTATGGGGAA?ACAAACATTC?TCATAATGCT?55680

GTGTTGTAAA?CAGGTATAAC?ATCTCAGGAG?TACATGTTAT?TGATATCAAT?CAACACTGCA?55740

AACGCAAATA?GCCTTTTGCC?TCGCACTTTC?GCTTCTAAAA?ATTTATGATA?TTCATTGATA?55800

AATTCGCTGC?AGTGTTGTTT?GTAAGGACAA?ACAGGTTTTT?TTTTTAACCA?CTCATCAAGA?55860

GAAGACTAGT?AAAATAAATT?AGACAAATCC?AAACAAGGAA?CACAACGCAA?CGACTAAAAA?55920

GCAGAGGGCA?GCTCCATGTG?GCTATCTTTA?TAAGTGTTGA?AGCCCAGGCT?ATAGCATTCA?55980

AGAAAATAAG?CAAGGTAGAG?ACCAATGTAT?AGAGTTACTT?GGGCTGGGTG?TCTTCTATTG?56040

CCCTTAGAGA?TCAGTTCTCC?ACCCTTGGTC?ACCAGACTGT?CTGCCCCAGG?AGGCTCATCT?56100

TTATGGACTA?CATCAACCGG?CTCTCTTGCC?CTCAAGCTTC?CAGTAAGTTT?GGCCAATGGG?56160

GTGACCCAGC?GGTATCTAAG?GGAAGCAATG?AGGAGCACAT?TTAAGGTATC?TGTGTTCTGG?56220

CTCCCTCTGT?GGAATCTTTT?CCAGCTGGCC?AAGTCCCTCA?CTTGGAGGTC?ACAGGTTCTC?56280

TTCAGGAGGT?CATTTCCAAG?ATTTACTTCT?TCCCTCTCCT?TGCCACTTTG?GGCCTAGCAA?56340

GTCAACATAG?CAATTACTAG?TCCTAAGTAT?CTGCACTATG?GTTTCTCCCA?TTTTGTGGTG?56400

GTTTCCCTTG?ACTCTATCCA?TACCTTTGTA?AGTACTTGTT?TTACTAAACT?CTCCTTAAAT?56460

CTCCCTAATT?TGAGGGTGCC?ATCTGCTTGC?AACTGGAACC?CTGGTTGACA?CACCACCATT?56520

TCTGTTTTGT?TGTTATTGCT?TTTATTGCTT?TTTTTTTTTT?TTTTCAGACA?GAGTCTTGCT?56580

CTGTCACCCA?GGCTGGAGTG?CAGTGGCGCG?ATCTCGGCTC?ACTATAAGCT?CTGCCTCCCA?56640

GGTTCACGCC?ATTCTCCTGC?CTCAGCCTCC?CGAGCAGCTG?GGACTACAGG?TGCCCAACAC?56700

CACGCTTGGC?TAATTTTTTG?TATTTTTAGT?AGAGACGGGG?TTTCACCGTG?TTAGCCAGGA?56760

TGGTCTCGAT?CTCCTGACCT?CGTGATCTGC?CCACCTTGGC?CTCCCAAAGT?GCTGGGATTA?56820

CAGGCTTGAG?CCACCACGCC?TGGCCTGTTA?CTGCTTTTTA?AAGGGAATAC?ACACACACAC?56880

ACACACACAC?ACACGTGCAC?ACACATGCAT?GCTTATATAT?TTAGACGGTC?TCTGGGAGTA?56940

GATGCAAGGA?CATGAGAATC?AAACATTATT?TGGCCCTGTA?AAAGGAAAAT?AAATAGGTAG?57000

AAAACTGAGG?TTGAGAAGCA?ACTTTTTATT?TCATACCCTT?CTGTTACTTT?TGAATTTTCT?57060

ATTATTTTTC?TGTACTTAAA?AAATGTTTTC?ATTATAAATG?AGCAAATGCA?AGGCAGATTC?57120

TGTCATGGCA?GATGCATGCA?GCTTTCATTC?AAGTGACAGC?CCCACATAGC?CTCTGGGCAC?57180

CAGGATCAGA?AGTGGAGAAA?CAATACCTAA?TAGGGAGACC?ACCATGTGGG?CAGAAAATAA?57240

AGAGATAAGC?TCAAAAGCAT?CAATTTTCCT?TTTCATGCAC?ATGTTTTTGT?AATACTAATA?57300

TAGTTTTTAA?AACCTGTCAA?GAATGACATA?ATCAATACTC?TAAAATCTCT?TAGAGCAGGA?57360

AATAATTCTA?GTAAAATACC?TAGTACGGGC?CGGGTGCGGT?GGCTCACGCC?TGTAATCCCA?57420

GTACTATACA?CACACACACA?CACACACACA?CACACACACA?CACACACACA?CATACATATA?57480

TATTTTCACA?CTGAAACTAC?CTACCATCTG?GCCAACAATT?AAGGATATCA?AATGTCTGGG?57540

ATACTCTCCA?CACAACAAGA?CATCTAAAAC?AAACACCAGG?TTGGTCCCTA?CCCTCCTATG?57600

GCTTATATTC?TAGTTTGAGA?GGCAACATTA?ACAACGGCAA?CCTCATGTGA?ATCAGTTACT?57660

TGCCTTTAAA?TGCAAACATG?AGGTCAGAAA?TGGAGACAGA?GCTGATACGG?GAAGTGTGTG?57720

TGTGAGTGTG?TGTGTTTATG?CATTTATGTG?TGTGATTTCC?TCATTTGGAC?TTGTTCAACT?57780

GAGGGAATTT?AGCTTTGTAG?GTTTGAGTTT?CACTAGCATT?TTGGCTCATG?AATTTAGTAG?57840

TTTGCTATGA?TTGCTTTAAG?AAAACTGCAT?AAACATAAAT?TTGTATTTAC?CAAACAAATT?57900

AAGGGATTAA?GGAATGATTA?CTTGTGTCTC?AAATGAATTC?ATCCAATGAG?GTACTTTAAA?57960

TTGAAATCTT?GGCTGTACCT?TTAAACTCAA?ATTTTTTTAA?ATGCAATTTA?CAAGGAAGTT?58020

TTTTTAGTCT?TCTACGGAAT?GAAACAAGCT?GTAGCTGAAC?GGAAAAATAA?TTGGCTTTCT?58080

CCAGTGACAA?ACATAAAATA?ACTGAGCTGG?AATTTCAATT?GCATCCTTTC?CTATTTAACA?58140

CTTACCAGCC?CCAATGACCC?CAAATAAATC?CTAAAAATGC?ATACTTGGTT?TTCTTGCTTT?58200

CTTGTATCAT?TGAAGAATGA?AGTACAATTT?GAGTCCCCCC?AACGCTTGCT?GAATTTTCAT?58260

TTATTTTTCT?GTTTTTTGTT?TGTTTTTGTT?TTTAGTGGCA?GGGGACCTCT?CTGAGATACA?58320

GGCCACATAA?CAGGAGACAA?AATCTAAACA?TTTAAAATGA?CTCTTGCAGG?TGGAAATATC?58380

TACACATTGT?TGCCAAAGGC?AGTATTTCAG?AATTCTAGCA?CTTGTGCCAT?ATTCAAAAAG?58440

CTGAAACAAT?TGTAACTTTC?TCAATCATGC?TCTTTCAGCT?CTAATAGGAC?CCAGTGAATA?58500

AAACAAATTT?CTGAAAGCTG?GGGAGAAGCA?AGCAGTTTAT?AGTAAATACT?GTCATCAATA?58560

CATGAAATTC?TTAAGTTTTT?CATTGATAAA?GCTCACTTTA?ACAGTGCCTT?TATCTGGCAA?58620

AGACTGACTG?CAGGGACTAT?GAGATGAGTC?AAAAACCAGA?ATGTAGGGTT?TGGGGCTGAG?58680

AAGAACAGGA?AGCCAGTTAA?AAAAGTTAAG?CCATATAAAT?GCAAATGGTA?TATTAGATCA?58740

AGTGAAAGAG?TAGAATGGAG?CACTATTTCA?TGAACTCTCA?AAATAATAAC?TTTATGCCTC?58800

TGCTGAGAAG?TGCTTTAAAG?TTGGTACTTT?ACCTAAAGTG?ACAGCAACTG?AGAAAACAAT?58860

TCTCCCTCAG?TTGACAGGAC?TTGGAGTGCT?GTAGCAACAA?GGAAATAATT?TATTATTGAA?58920

AATAAAAGAT?GATTAAATAA?CTCTCTTGGT?GATGGTCAAA?ACATTGGTAA?ATGGCACAGA?58980

CTGATAGAGG?CAAGATAATG?ATACACGACT?GACGGAGTTT?TACAACATTC?CAATTCAACT?59040

AAAGTAATTT?GTTACTTACC?AGCAAAATTA?GTCAACCTAA?ACGAAAATGT?GCTGCTTTCT?59100

GACAGCCCTC?ATATTTAAAC?CCTTGAGGGA?AGGGGGACAG?GATAAGACAT?GGTCCTTTCC?59160

TCAAGATCTT?TAAGTTCTTC?TAGGGAATTT?TTAAAAATGC?ACGAAATGAT?TTTCATCAAA?59220

AGAGCTTTGG?AAATAAGGAT?GGTCTAAATG?AAGATGTGCT?TTTTAATTAA?GTTATTCATT?59280

TAGGATTTAA?ACAATTCTTT?ATCTCAAAGT?ACTGAGGCAG?CTTAATGGAA?AATGCAGAAA?59340

CTAACACAAA?ATCTGGTAAG?AACAGATTTT?TAAAAGATAG?TGACTATTAG?AGAATCTGAA?59400

AAATCAGCCC?CTGAAATGAA?CCATTTGCCT?CAACTAAGCA?TGGGATTTGG?TCCGAATATC?59460

AATGTTCTGT?GAGAGCAGAA?TTTTCACTGA?TAAATTTCTC?CGTGGAGGCT?TTTGCTTCAG?59520

TTTTTCAAAA?TATGCTGCGG?GGTTCTTGTG?CATGCCTGGT?ACCTGAAAGG?TTTTTCAATT?59580

ACAGTTTTAT?TAAACATGTG?AAAATATTGG?TCAAAACAGA?TGATTTCCAT?ATTTTCTCTG?59640

GAAAAGGGCC?AGAGTACTAC?CATATTTGGG?AAAGGCATCC?CTTTAAAAAG?TAATATAACG?59700

AGGTCCAAGG?CGCTTGGTTT?CTAACAACCA?AATAACTTGG?GCACAGACTG?AGAAGCTAAA?59760

GCAGAAATTG?CTACAGTGGG?TACAAGAGCT?GGATACAGAG?CACAGATGTG?TTCTGTTTGG?59820

CCTGAACTCT?TTTCTTTTTA?AAATATAAAC?CAAGTTTTAA?AATTCAGAGA?TTTCACATGC?59880

AAAACTGGTT?TTCTAATTCC?ACTTAAAGAA?ATAAAAAAGA?CTTGGAAACA?GTGGGCCCAC?59940

ACCATCCCAA?GACAACAGTC?AGCTGACTGT?GAGCTGAGAT?GCTCCTCTTG?AGAAAGTCTC?60000

TGTGTCCTCA?AATTTGCCTC?CTCCCTGACA?CTCCTTCATG?TCACCTACTC?CCCTGCCAGG?60060

CCCCTGTGGC?CACCTGAATG?TTTACAATTA?ATGATTATTT?CACCTGCACA?TTCAATTCTC?60120

TCTTCTAATA?TTAGGGTTTA?ACTAGAATGC?AAAAAGTCAT?GATTTAACTC?TCTAATATGA?60180

ATATTTTTAA?CATGCATGTA?ATTCTCTAAT?GTGTATAATC?ACATTTCAGT?TCAAGGCCAG?60240

AGGACATCTA?CTTTAGAAAT?CAGATCTATG?TGATGTTAAT?AATTATTATT?ACCATGATCA?60300

TGATTTATCG?AATGCAGACC?AAATGCTTAG?TCCAGTATTA?AGTACTGTGA?TGATTATTTC?60360

ATTTACTTAT?CACAACCACC?ATGCAATTTT?GTCATTAACA?TTTTATAGAT?GGAGAAATTA?60420

AGGGTCAAAG?AGATGAAATA?ACTTATCATA?TCATATCAAT?GAGAGAAAGC?AAATAAAAGA?60480

CAAAGCCAAT?GGTGACACAC?AAGCCCTCAT?CCTTCCTGAT?ACTCCACAAT?GAAATAGATA?60540

TTCCATCAAA?AAGTTTAAGA?GTAGAACTTT?ACACACATTC?CAGTACAAGG?CAAAGACACA?60600

GGTGTGACTA?CTAGGAGTTG?AAGAAAGTAT?ACAAGGGGTG?GGGAAGCAAT?AAGTTTCTTA?60660

GACAAAAGCT?TTGGTTCTTT?GTAATTACTT?CACTTATTTT?AGGAGACATA?TATAATAAGG?60720

TCAGCTTGGT?GAAGCCCAAG?AGTTTTAAGG?TAAAAACTTG?AGTGTGAATT?CAGGCTCTTA?60780

CATGTATTAG?CTGTGGGCCA?CTTAACTTCT?TGAAACCTCC?ATTTCCTGAT?TTATGAAATC?60840

GTCCCATGTA?GGATCATGAT?GAAGAGCAAA?CATGCTTGAA?GTACCTGTGA?AAATCCTCTA?60900

GACAGTAAAA?AATGCCACAC?AAGCATTCAC?TTGCTAGAAA?GGTAACATTC?CATGCAATGC?60960

TCTCTCACAC?CAAAGAAAAT?TGCAGGAAAC?AAATGACAAG?ATAAGTATGA?GTTTGGTAAA?61020

TCTATTCCTA?CTCATCAATA?GAATGTAGCA?GTTTGATGAC?TTCTAAAAAA?CCTTTCAGGA?61080

AATTTGAATG?AATAGACAAA?TTGAAATATA?ATAATTTTTT?GTTACCACTG?TGCCCTGATG?61140

CTTTCAAATA?TACAATGGAA?TCAATCATCG?TTACAATAAA?GTTGCCAAGA?GTGTTTAGGA?61200

TCTAGAACCA?AATAATCTGG?TTTTGAAATA?TTGTTCATAA?CCAGCATAGG?TCTGGCAAAC?61260

AGGCAGTAAC?TTGAGAATCC?AGTTCAATTT?TCAAATCCTC?TGCTTACTCC?TGCACATTTA?61320

TCAGGCGAGA?GCTGATCTAC?TTTGGCTTTG?AGACACTTAG?TGTGTTATTT?CGCAACATGC?61380

TAATAAAATT?AGTAAGTTTG?ACATGCAGAG?ATGGGAAGGC?AATGATGTGT?CTTAAGATTG?61440

TGGAATTCTA?AAATATTGAA?ATAAAATCAT?GTTTGGCTTA?CTTTTCAAGG?AAATAAAACT?61500

GCTGTACTTT?CATTCACAGC?TGATGAAAGA?ATTACAGAAG?AATATGGGCA?ACAACAATTG?61560

TAGTAGATTT?TTAAGTACCT?AGTTAAAAAG?TGTTCTGGGC?CATCCAGATA?TATGGAAAGC?61620

AATATTCCTT?AATCTTCTCT?CCTGGAGCTC?ATTTGCTCAC?GTAAAAGTTA?ATTATAAAAC?61680

ATTGCTATAT?GACTTCTACT?GGAGGAGAAT?TCACCATGCT?GGGAATGGCA?GCAGGTTGCA?61740

GTGGAGAAGG?CTCTGAATCG?ACCATGAGGG?GGCTTTGAGT?TCAAGGGCAA?TTACCCAACC?61800

ACTCTCTGTG?CCTGTTCTCC?AACCAGTCAA?ACAAATGGGT?TGGACATGAT?GAACTTAAAG?61860

GTCCCTTTCA?TTTTGAAAAA?TGACACAAAA?AGGACAGAAA?GACACATTCA?GATTCACTTT?61920

GGTTTCTAAG?ATAACACCAA?ACACTTTGAA?ACTTCCCCCT?TCATGTTTTT?CAAGCAGAGG?61980

AAGTAAAAAA?AAAAAAAAAA?AAAAAAGAAA?GAAGTTGCAA?GTATTGTTAA?GGCTTCTAGA?62040

AAGGACAACA?AAGGGCAGGA?AATTTGAAAC?AAAATCTGAG?AATCTGCCCT?TAAACTGGGC?62100

AATTTTGCTT?GTTTTCTCAC?AGTGCAGTTA?GATGAAAAAG?TGTAAGGTTG?ATCTTCGCCT?62160

TTCCTGGGCA?TTACTCATTG?CTGTCATGAC?CTTGATGCAA?TTTGCAGTAA?ACATCATAAA?62220

GGTCTCTCTT?GTGGTGAGTA?GCTGCAACTT?TTCTGATGCT?ACCTCCTGTG?ATTAAAATAT?62280

CTACTCCCGG?CCTGGCACGG?TGGCTCACGC?CTGTAATCCC?AGCACTCTGG?TAGGCCGAGG?62340

TGGGTGAATC?ACGAGGTCAA?GAAATCAAGA?CCATCCTGGC?CAATATGGCG?AAACCCCGTC?62400

TCTACTAAAA?ATACAAAAAT?TAGCTAGGGC?TTGATGGTGC?GTGCCTGTAG?TCCCAGCTAC?62460

TCAGGAGGCT?GAGGCAGGAG?AATCACTTGA?ACCCAGGAGA?CAGAGGTTGC?AGATGGCCAA?62520

GACTGTGCCA?CTACATTCCA?GCCTTACGAC?AGAGCAAGAC?TCTGTATTTA?AAAAAAAAAA?62580

AAAAAAAAAA?AGGCTACTCC?TTTCCAAGTC?CTAGCAATCC?CACTAAGGTT?GGTAACTTAG?62640

TCTGTTTGGC?TGCCATACAA?AATATGTGAG?ACTGGGTGAT?TTATAAAGGA?CAGAAATTTT?62700

TCACAGTTCT?AGAGGCTGAC?AAGTCCAAAA?TCAAGGCACT?GGCAGTTCTG?ATGTCTCGTA?62760

AGAGCCCCCT?TTCCTGCTTC?CAAGATGGTG?CTTTGTTGCT?GTGTCCTCTA?GAGAGGACCA?62820

GTACTGTGTC?ATCACATAGC?AGAAAATGGA?AGGGCAAAAG?GATCCAGGCT?GGTTACCTCC?62880

AGCCCTTTTA?TGTGGGACTA?ATCCACTCAT?GACTTAATCA?CTTCCCCCAA?ATCTCCGTCT?62940

CTTGATACCA?CCACAATGGG?GATTAAGTTT?CAACATAAAT?TTTGGAGGGG?AGACATCAGC?63000

CACAGTAGTT?GGTGAGAAAA?AAGGACAGTA?TTTACATAAT?GACAGTTGTC?AATGGGCTGT?63060

GGAAAAGTCA?AGATAGATTC?CAGCAGTGAT?TTTAAGATGG?AAAATGAGAA?CCATGCACAC?63120

AGTCTTCAAG?GTGCAATCTT?CCAACATAGT?TCTGGAACAC?AGCTGGCTCC?TTCCATCCAT?63180

GGGGAATGAC?CACATTTGTG?TGCTGAAATA?ACATTTAGTA?CTAGAGATAA?AACTGGAATA?63240

AGTGATCTAA?ACTTTGAAAT?GTTTTGAATG?ACCTTTGGCT?ACAAAGTCAA?ATTATAATGC?63300

TTTCTATTTC?TTAAGACAAC?TCTTTATGGA?AGTTCTAGTA?TGTACCTAAC?TTTGGCACCT?63360

TAGATTTGCC?CCACACTGAA?TCTTATCTAT?TAAACCTATC?TCATTCTGGG?GTGAGAACCC?63420

AGATGTGTAA?AATCGTATGG?CCAGAGGTGA?CTGAGAAGTG?CATTTTGACT?ATGTTTCATA?63480

GTCTTTTATC?CATCTTAGCA?TAATCTTTTT?ACCAGCACCA?GTGGAGTTGT?GAACTCGCTC?63540

AATTTCTTGT?GATGTCCAGT?GTAAAAATGT?ATGCCTATAA?ATGTAACTCT?TAGAAAGAGA?63600

AGCAAAAATG?AGAAACCATG?GGGGAGGAGG?GGAGGAAATG?ACAAGCACAG?TCTGTTTTTA?63660

GGACACTGTA?CTTGCTGTTC?CCTCCAACTA?GAATGCGCTT?AACCCAGAGA?TCTGCCTTCT?63720

TCATCCCGAT?TTCATACCAA?TTACTGCTCA?AATATCACAT?TATCAAAGAT?GCCATTCTTG?63780

ACAACCGCTT?CTAAAATTAC?AAGCATCTAC?CATTGTTCTC?AGACCCTCGC?GCTGTACTTA?63840

TCTGCTGACA?TGTTGATAGA?ATCTTGTTTA?TTAGCTTGTA?CACATGGACT?TTAATTCACT?63900

CTGTATTCCC?CAAATCTCAA?ACATTGGCTG?GCACACGGTG?GTTGGTACTC?TATAAACACT?63960

TGGTGATGGC?TTTCCTATCC?CTAAGTCCTC?CAAAGCCAAG?TTTCATACCT?CTTCCTTAAG?64020

TTCCAAAGGA?AACCTTATCT?GCAGAAAATT?AATGCATATT?TGCTGTTGCT?GGATAAAGAA?64080

TAAGGATATA?GTCACAGAGA?AAAAAGGACA?TGTTGAGGCC?AGGTATGGAG?GGTATAAACA?64140

GTTGGTGAAG?AGTTTTAAGC?TCAAGGCCTA?GCCTGTCTAA?CTTAGCAATA?AAAGGAAGTC?64200

AGTTCTGAAG?TCAAAGAGAG?TTCTTCTTTC?CCCACTGGGA?GGAGCTGGTT?CATGAAAGTG?64260

GAGGGCCAGA?GCCAAGAGAA?CTCTCCCAAG?ACACATTGTT?CAAAAGTCAA?GGGCATAATC?64320

TAGATAGAGC?TACACAGTAG?CCATGAGGAC?ACATGGATTT?ATAAATTTAA?ATTAACTAAA?64380

GTTAAATGAA?ATCATACATT?CAGTTCCAAG?TCAGACCAGC?CATTTTCAAG?TGCTTAATAG?64440

CCACATGTGG?CCAGGAATAG?ACAGGATACT?TTCATCATTG?CAGAAAGTCC?TATAGGACAA?64500

CACTGATCTA?AAGAAATTCA?AAAGGACCTG?CGTTCCTCGG?CTTCTGAGGA?GATCTGAAAA?64560

CGAAGGCCCA?GAGGGAAATG?GAAGGAGAAG?CAGGGCAGAG?CTTGAAAAGT?AATCGCATTG?64620

GAAAGGGCCC?TGACTGCTGG?CTTGGATGCC?TTGTGTAATT?AAAGTTCTAT?CCCAACTTCT?64680

TAAGGAATGA?GTCTCGTATT?AAATGACTGG?CTGTCTGTAG?TGTCACTGCT?GAGGTAGGGA?64740

GAGAAGACAA?TTAGGGACAA?GGAGTAGTGT?TCCATGGAAA?ACACGTTAGC?TATGAGTGGC?64800

AGCAGCAAAA?GGTCTCAGAA?GTGAGAGAAA?TGGACCCAAC?TAGGTTTGCA?ACAAGCTGAA?64860

ACCTGTAAAG?GCTCATGTCA?GCTGGCACAA?CCTCTCAAAA?TGCAAATCCC?TGAGCCCAAG?64920

ATAAATGTAA?GGCTCGTCTG?ACTCCTAAGG?TATCAAGTAA?TTCTTATTAA?GCCCCATTTC?64980

AATGACTGAA?ACCTAATGCA?GAGCCCAGGC?ACACAGATTA?AGTTTCCAGT?CAAAGCCCAC?65040

ACAAGCCTAA?AGAAAGGAAA?TTAACATTTT?AGAGAAAAAA?AAAAAAAAAA?AAAAAAAAAC?65100

CCACAGGCTT?TTTCAAAGGC?TTTTTTTTTT?TTTTGGAGGA?TTTAAGTCAC?AGCATGCCAA?65160

ATAAAGGTGA?GTTTCTAGGA?GAATACAGCA?CAGAGGTGAC?CAAGGTGGGT?GAAATTTATT?65220

CACAGGGGAA?AATCCAAATG?CCTTCAGGGA?AACCACTTTT?GCAGGGTTCT?TCTGATAAAT?65280

ACTGAACCCA?ATTAAAAGCA?TCCCTTCAGG?GCAAGTTTTC?TCCTAGGAGA?TTTCTATTGG?65340

CCGCTTTAAC?TTCCCTTTCC?CCAGAATTTC?CAGGAGAAGT?TTGTAACGGT?TTATAATCCC?65400

TACCACTCCA?TGCTCATAGA?CTTTAAGCAT?ATTTTTCTCC?CACAAGGCAG?TACTATTTTT?65460

ATAATCCTTT?TAAGATTAAA?ACTAAAAACA?CAGATGATTA?AAAAAAAAAA?AAAAAGGCCT?65520

GGCTGCATCC?TCCTACAATA?AAGTATTATA?ATTGCAGTGC?ACTACTAAGT?AGTATTTCCA?65580

CAAACATTAG?ACTATCTGGT?TTCCAGGACA?AAGAAACAGC?CTATAATTCC?AAAGCACAGG?65640

AATGGAAAAG?TACAAGTAAT?TTAATCTGTC?CCACTGTGAT?TATAGGTGCT?AAGAAATTAC?65700

CTGAACGGAC?CTCTTTGGGA?CTTGAGAAGA?ATGGGGACTT?TAATGATGCT?CCATAACTGC?65760

CCTATTCATT?ATGATACCCA?AGAGCCACCT?GTGGCTATTT?AAATTCAAGT?TAACTGAAAT?65820

AAAAATATAT?CTATATTTGA?AATTCAGTTC?CTTATTTGCA?CCTGCTACGT?TTCAAGCCAC?65880

ATGTATCATC?TAAGATGGTC?TCAGACCCAC?TGTTCAATAG?AACTTCCTGC?AAAGGTGAAA?65940

ATATCTTATA?CCAGTGCTGT?CCTTAAACCT?TAACACAGCC?GAGGTATAAG?ATATTTTCAT?66000

CTCTGCAGAA?AGTTCTATTG?AACAGTGGAT?CTAAGACCAT?CTTAGAGAGA?TAATTACATA?66060

ATTTTTCCCA?ATTTCATAAT?AGAGATTATG?AAGTAACAGC?CTCCAAAATA?CAGGGTTTTT?66120

AGGCTACTGG?CTACCTTCTA?CACTCAGGTG?AACTTTTTGT?AGTGGTTTAC?ACATGTGTAC?66180

CAATTGCCCT?CATCTCCCCA?GTTTCAAGTA?CATTAAAATG?GCATTAGATG?TAATAAAATA?66240

CATGCCACTG?AGACTCAGCT?CAATTGAAAC?TTGAGTTTCT?TCAGAATTCC?AAACGATGGT?66300

GCATCTCTTT?CTGAAACCTG?AAGTGGGGAC?TTGTCAGGAA?AATGTCTATG?AGGGAGGCCT?66360

AGGAAAAAGA?AGGCATTTTC?CAAAATTAAT?AAATTTATTT?CCTTGTTTTT?TGTCACACCT?66420

TATTCCAGAG?GTGTCTCTAG?GCTACTGTGT?GCGGAACGAG?GTCTGGACAG?AACCTAATGA?66480

TAAATTGGGG?GATACTGAAA?GTCCTGGCAC?TCTAAGGAGC?TTCCCCACAC?ATCTTTAGAT?66540

TTTTATTTCC?CATGTGGGAA?AAAAAGAAAG?GGATTTCCTA?TCTTCCCATC?ACAAACTCCT?66600

GGCTTTGCAG?TGGTTTTATT?ACGTCATTCC?CCTAGTTACA?ATCTGCCAGT?GACTCAGAGA?66660

ATTTAGCCCA?AACTGGCACT?TAAGGCTCCC?ATAATCTGAT?TACCTTTCTG?CTGAATAACT?66720

CCTTTTATCA?GAAACCCTTT?GACCTGATAA?TTGCTGGCTT?TCCTACCACC?AAAATTTCTA?66780

CCTCCCTACC?AGATCTATCA?GGTGGATTTT?AAGGTCAAGA?AGAGCATGCC?CAAGGCAGCC?66840

TGCTCAGCCC?CTGGAAGGAG?TTCAGTGCCT?TCACTGTTGG?CTGTGAGGTT?TACGTGATGG?66900

AGGGAAGAGA?CTCCAAGAAT?GGTGTCTGAA?AGGATGCCTG?GTGTCTGATG?CTGCCCCTCA?66960

GGAGTGGTCC?AAGGTGGTTC?AAATACTGCC?TGCTTTGGCC?ATGGCTGACA?GAGCTGAAGA?67020

ACTGCCTCTA?TATGGTGTGT?GGACACACAC?CCCAGGCAGC?CACTTGCCGG?CTTCCCTCTG?67080

TTTCCTTGAA?GGAAGTGGAG?TAGCATGGCC?CTGGGGCTAA?CAAGTGAACA?ATAGTGCCTG?67140

CCTTAAATCA?TACCCAGCCT?TTCAGACCCA?GGTCAAGTGT?TTTCTCTTTT?GGAAAATCAT?67200

CCATTCCCCC?CACTACCAGC?CCCACCAAGA?GTACTCTGCC?TCCTCCGGTT?TTGGTTTTTA?67260

ACCATCTTTA?CTGTGAGGTA?TGCTTTTAGA?TAGGCCTGTA?TTTGCTCTGT?TCTGCAGATG?67320

AGTTTCCAAA?ACCTTCTAAA?ACCTTGCTCA?TATTTGTTAT?GCTGGATTTA?AAGTCAACAG?67380

ATGGGAGTTT?TCAACCCAGT?AAATGGAATT?TCTTTGCTGT?GGGAAATCAA?GTACTTTGAC?67440

CTCTCTGGTG?AAATTCTTCA?TTTGTAACCT?CACTGGGTTA?GGCTAGATTA?GTGTTTCTCA?67500

ACATGGTTCC?ACATCGGAAT?CATCTGGGGA?TCTTTTAAAA?CAATAATGAT?GCCAAAGTCC?67560

TACCCCAGGG?CAATGAGTCA?GAACTTCTAG?GTGCTTGGCT?CAGGCTTTGG?AATTCTTTTA?67620

GAAGTTCGCA?GGTGATCCTA?ACGTGCAGCC?AGGGTTAGAA?AAATAAACTG?AGTTCAGGAA?67680

GGGACTTATG?CTACATGGAC?TGGAGAATTC?AATAGGAAAA?AATGTAGTAG?TTAGAGATGG?67740

GGCATGGTAG?TACTGGACAG?AGGCAGTCAG?GCCCATAGGT?GTTGCTTCTC?ATCTTTGCCT?67800

TGAGCTGTAA?CTAGAAAAAC?TGCAAACTGC?ATTATAACCA?GAACATTATT?ATATACATAT?67860

ACATGTACAA?TCAAGCCCAA?CCCAATTAAT?TTTCTCATAT?GACTCAAACT?CTAGTACCAT?67920

TTGGAGATGA?GGCAGGAATC?ATAAACATAA?TTGGCTGCAG?GGCATTTAGT?TGCCATTGTA?67980

TAAATTCTTC?CTGAAAAATA?ATTTTAGATT?AATTTTTAAG?TGTGGATTTT?ACAATTTCCT?68040

ATCTTTTTAA?AGGGTGGGAA?TCCTTTGCCA?ATTCCCAAGA?GGACAATAAG?CTTAAAGGAA?68100

GATAATGTCT?GAAAGATCTG?AGGACCAAGT?TTCCTGAGAA?AGCTGTATTT?CTAAAGTTTT?68160

GACCCTACAA?GGCAACATTA?AAAGTAAGTT?CAAGGAAACA?AATGTGAGAA?AGCATATCTC?68220

CCTTTAGATA?ACCTAGCAAA?GAAGTTAAGA?AGGGAAATAG?TTCCTTAGAT?CAGAATTAAC?68280

AGTTGTGGAT?AGCCTTCCCT?TCAGAAAATT?GCAATGCTAA?ACAGACGTTA?CACAAGCAAT?68340

ATATCCCTGC?AACTTAATTT?CTCTTCCTAG?GATCTTTAAT?ATTTTTCTTT?TTTTATTCCA?68400

TTAAACAAAT?ATATATTGAG?CATCACCTAT?CCACCAGATC?TGAAGAAACA?CTATTTTTAA?68460

TATGTTCAAA?ATTTGAGTCT?TTTCTTGATA?CAATAACATC?TGCCTTAACA?GGAATCAGTA?68520

TGTAAAAATT?ACAGTTTTTA?AAGAATTATA?TAAAAGGTAT?TATTCCAGAA?GACTTGCTAT?68580

GGAATCCCTT?TTAAAAAGGG?CGTTCAGAAA?AAGGTAACAC?TGAAATTTAT?TACAGTTTGA?68640

AGAAAATCAC?TCCAATTATA?AATCCATGAA?CCCAGTCATT?GTTTAATGAA?GCTCATCTTT?68700

GCTGGAAAAT?CCCCACTGAG?AACAAAGCAT?CACAATGATC?CACACAGTCC?TAATCAAGCC?68760

CACTGGAAAA?ATCACCCTGA?AGAACACTGG?TGGAAAACAG?AAAGAAGTCC?ACACCACAGT?68820

GTGAGAGCTA?ATTTAATGTG?TTCTTCAAGA?AAAATTAAAT?AAAACAATAT?6ACTCAATTT?68880

TTCTTTTATG?TTGCAAGAAA?AATAACATTT?ATATAAAGCT?AGTAGTAGAA?AAGCAGAAGT?68940

ATAGCTTAGC?TTTCTATGAT?GGCAAGTGAA?ATAGTTTCTG?CTAATCAAAG?TGATTCTTTT?69000

TTTTTTTTCC?TTTGAGACGG?AGTCTTGCTC?TGTCGCCAGG?CTGGAGTGCA?GTGGCACGAT?69060

CTCAGCTCAC?TGCAACCTCC?GCCTCCCAGG?TTCAAGTGAT?TCCCTTGCCT?CAGCCTCCCG?69120

AATAGCTGGG?ACTAGAGGCA?CGTGCCACCA?CGCCCAGTTA?ATTTTTGTAT?TTTTAGTAGA?69180

GACGGGGTTT?CACCATGTTG?GCCAGGATGG?TCTCAATCTC?TTAACCTCGT?GATCTGCCCT?69240

CCTCGGCCTC?CCAAAGATCC?GGGATTACAG?GTGTGAGCCA?CCGTGCCTGG?CCATCAAAGT?69300

GATTCTTAGC?CATTTTCTTT?GAAAATGTCA?GTCATAGAGG?TAGGCTCTGT?TGCTCTTCAA?69360

TGTATACCTT?CTTTTATATA?AAAGCAATTT?GACTAAATAT?TAGATGTCTG?TGTGAGTCGT?69420

GTTCTGCTAC?TCAAAACACT?TCTTGTTCTG?TTCTTCTCTA?TATTTTGTTT?ATTTGTTTGT?69480

TTTTTGAGAT?GGAATCTTGG?TCTGTTGCCC?AGGCTGGAGT?GCAATGGCAT?GATCTCGGCT?69540

CACTGCAACC?TCCACCTCCT?GGGTTCAAGC?GATTCTCCTG?CCTCAGCCTC?CCGAGTAGCT?69600

GTGATTACAG?GCGCCCGCCA?CCATGCCCAG?CTAATTTTTG?TATTTTTTAG?TAGAGATAGG?69660

GTTTCACCAT?GTTGGTCAGG?CTGGTCTTGA?ACTCTTGACC?TCAGGTGATC?CACCTACCTT?69720

GCCCTCACAA?AGTGCTGGGA?TTACAGGCAT?GAGCCACAGC?GCCCAACCTC?TTCTCTGTAT?69780

GTTTATTCAG?ACATTCATGT?TTAAGAATTT?CTGAGAAAGG?AAGCCAAAGA?TAATAATACC?69840

TGACCTCTAT?GTCTATATGA?TGAAGAAGTG?CACTTCCTAT?GTAAAGATGC?CCGTATTCCT?69900

GATTAGGTTA?AGCAACTTGA?AGTTCTAGTG?AGGGGCAAAA?CTACAGGACT?GCAGAAACTG?69960

GCATAGCCTT?TTACACATGG?CAGCATTTGT?CTACTGATAA?TGGTGACACA?ACCTCCAAGA?70020

GGGCAGACCA?CACGGTGTAT?TAAAGAGAAG?CTGTCCCCAT?AAGAAAAGGG?GAAAAGTAAA?70080

ATGACTCATT?ACATAGTTTG?AAATCTCTTA?TGATGGGTGG?ACAAAACCCT?CAAAGAAGAA?70140

ATTCTCCAGT?CTTAAATTGG?GCTTTTAATG?TTCGAGGCAA?GAACAAGTCT?CCTGATGAGT?70200

ACACTGCCAT?CGCCTCTTTA?ACAATTTAGC?TATGAAAATA?TGAAAATACG?AGGAGACTAT?70260

AGATTTTTAT?CTTAGATTTA?CTTACAAATT?AAGCAGTGAG?GGAGCATGAC?TAAAAATAGA?70320

AAAATGATGA?AAAGATTAAT?TAATGATACT?TTACTATGTC?TCAGTGGATG?GGCAGTCCTA?70380

TTACAGCTGG?GGCAGATGAT?TTCATCTTTC?TGGGCCTCCA?TTTCCACATC?TGTAAAACAG?70440

GATAATTATA?TCCATCTCAG?AGAGCTGTTT?TTAAAATTAC?AGATGACAGG?AAAGTGAAAC?70500

TGTTTTGAAA?ATAATGAAGC?TTTCTATTAC?TGTGAGATTA?TTAAAAGATT?ATTATAACTA?70560

GACATGGTCA?ATATGTTTTC?TTCAAAGTTA?TCAGACTAGA?CATTTTTCCC?TCTGGTGATC?70620

TTTCACCCAT?ATGTCTCAAT?CATACTGAAA?TTATTCAAAT?CACTTCTTTT?TTCTGTTTTC?70680

CTGGTACTAG?TTTCTCTTTT?TCTTTTTCTT?TTTCCTTTCT?CTTTTTTTTT?TTTTTTTTTT?70740

TTTTTTTTGA?GACAAAGTCT?CGCTCTGTTG?CCCAGGCTGG?AGTGCAGTGG?TGCGATATCG?70800

GATCACTGCA?ACCACTGTCT?CCTGGGTTCA?AGTGATTCTC?CTGGCTCAGC?TTCCTGAGTA?70860

GCTGGGATTA?TAGGCGTGTC?CCACCACTCC?TAGCTAATTT?TTGTATTTTT?AGTAAAGACA?70920

GGGTTTCACC?ATGTTGGTCA?GGCTGGTCTC?AAACTCCTGA?CCTCGTGATC?CGCCTGCCTC?70980

GGCCTCCCAA?AGTGCTGGGA?TTACAGGCCT?GAGCCATTGC?ACTGGCTGGT?ACTAGTTTTC?71040

TATCTGCCTG?AAGAAGTACG?CAAATGACTA?TTTTCATGAC?TTTTTTTTTT?GCCTTTAATA?71100

TTATTTAACA?GCTATTTTAA?CAATGAAAGA?CATTTTACAT?ATTCTCAAAA?GGTATGTACC?71160

AAAGAAGGGT?GTGGGCAGAA?ATGTTCACAA?AATCAGGACC?TTTCATTGCA?TCTTGGTGAC?71220

CACCAATAAA?GTACACAGAA?ACCCATAGTG?AACTGAGGTC?TAAGTGGCTG?CTATCAACCA?71280

ACACAATCTT?GAACTGCTGA?GTCTGATCAT?TTCATTTTCT?TAAAACTTCA?GGACAGTTCA?71340

ATTTAGAGAG?CACAAGAGTG?AAGTTAGCCT?CCCTGGTCAT?CTAAAGCAAC?ATGGGAAGGT?71400

AATTTAAGAA?AAGTGACACC?ATATCAATCA?CTTTCCCAAG?CTTTTCAGGG?GCTCACTCCA?71460

AAGACTTTCT?TGATGATAAA?TTTTATTAAA?GTGCTGATCA?TAATCAAAAC?AGTACATTGT?71520

ATCAGAGGTC?AAGCATTGTT?TTTCACTTCC?CTTCCCAGAA?CTTATTAAAG?ATGTACCTCT?71580

GAAGAAAGAC?ATAAGGAAGA?ACAAAATTGT?TTTGACTCAC?AGAAAATGGC?TTACACAGAC?71640

ATCTAATACT?TAGTCAAGTT?GCTTATATAT?ATGAAATAAG?TTATACCTTG?GGAGTAACAA?71700

AGCCAATAGG?CTTGGCTCAT?AGGGGGCTAA?CTACGGCTGC?AGCAGTTATT?CAAGAAGTTA?71760

ACATATTCTC?TCCTGTCCCC?TGAAGACACC?ACAGGCATCT?CAGTAATAAA?CTGATAACAA?71820

CCAATACTCA?AGAGTTTGTG?AAAATGCTTT?GTAAAGTGCT?GAATAATGTA?AGTGATTATC?71880

TACTTACCAC?AAACGTCCTC?ACCAACATCA?TCATTAAAAT?CTTGAAAGAT?AAGTGCTTTT?71940

CAGTAGTTTT?GAGAGTGAAC?CAATGACATG?CTAAATTAAA?AGCATTATAT?TTCAACCATT?72000

TCCAATAAGT?GCCACAGAAT?ATTAAGACTT?AAGAATATTA?AAATTCTGGT?CAGGTGCAGT?72060

GGCCCATGCC?TGTAATCCCA?GCACTTTGGG?AAGCCGAGGA?GGGTGGATTG?CCTGAGGTCA?72120

GAAGTTCAAG?AGCAGCATGG?CCAACATGGC?AAAACCCTGT?CTCTACTAAA?AATACAAAAA?72180

TTAGCCAGGT?GTGGTAGTGG?GCACCTACAA?TCCCAGCTAC?TCGGGAGGCT?GAGGCAGGAG?72240

AATAACTTGA?ACCCAGGAGG?CAGAGGTTGC?AGTGAGCTGA?GGTCGTGCCA?TTGTACTCCA?72300

GCCTGGGTGA?GAAGAACAAA?ACTCTGTCTC?AAAAAAAAAA?AAAAAAAAAG?AATATTAAAA?72360

TTCTTATTTC?ATCTCCTTTT?CCTCTATAGA?TAGAGCAGGT?AGGGCACTAC?CAGTCCAAAT?72420

CTATGTAATG?TGATGTCAGT?GGTAGCTCCA?GAATTCCCAT?AGAGGAGTGG?CTACATGGGT?72480

GATGATCTGG?CTGAAAGGGA?GGCAGGCAAC?ACAGCTGGAA?GCTGTGCTTG?CACAAGAGAA?72540

CACTACTTGT?GGTACCTAGA?CTGCATGTTT?ATTCAGGATG?GATGGGGACT?ATGGTGGACG?72600

AGAAGGCTGA?AGGCCAAATT?CAAGACCATC?CTTAGAAACC?CACTCCTATT?AAGCACCCAG?72660

GTAAGAAAGG?CCTCATATTT?AAGTCTCCTT?AGCATGTATC?ATTTTAACAG?GGCTTTCCAA?72720

AAAGTACAAC?CAGGGGTCAC?CTTTGCAATA?TGGGATTATT?TACCCTCAGG?TAGGTAGAAG?72780

AGTATCTTCA?GCCACTCTTC?ATTGCACCAA?GACCCCTTCA?GCCATCCCTA?TTCCAGCAAT?72840

CCCAATGACT?GAAATCATCT?ATGACTCATA?AAGAGAAAAG?GCAGGAGTGA?CAAAAAATTG?72900

TCCTGCGTGA?GATGGTGTGA?TTTACTTTAT?GACTTTGCCT?GGTCTCTATA?GTCATAATGC?72960

ATTGAGCCTT?CTGCAAAAGA?TTCACACATG?AGAGAATAAA?TGAATCAAAG?GCAGAGCCAG?73020

TGATGGATGG?AAAATTAACC?TTAACACCCA?CACACCACAG?CTCCCCAAAA?TTCACAGAAA?73080

CTAAAGACTG?CAGACAGAGC?AAGTCTCCAC?TGTAAAGAAC?AATTTACACA?AAGCAGATCA?73140

TACGAGATTT?TCCATAAGCC?TATGGTTCTG?TCAAACAATA?CTACAGGTGG?CTTTAAGCCA?73200

TTGACATTTA?CACTTGGTGG?TGAAAAGCCA?TCTGGGAGAA?AAAAAAATAG?CACTCCCCGC?73260

CTTGGATCTA?AAAGCAAGTT?TCCTCGGCCT?TTAAAAGCAA?TGAATTCCAA?ACAGCAACAA?73320

ACAAAACACA?TAAACAGAAT?TAGTGAGAAT?CTGTGCTAAG?AGCTATGGCA?AAATCAGACA?73380

GAAGTTTCTC?CCTCAAAGAG?TTTTCATTCT?AGTAAGAGTT?TTGTTTTGTT?TTGTTTGTTT?73440

TGAGACAGAG?TCTCACTCTG?TCGCCTAGGC?TGGAGTGCAG?TGGCGCGATC?TCGGCTCACT?73500

GCAAACTCCG?CCTCCCAGGT?TCACGCCATT?CTCCTGCCTC?AGCCTCCCGA?GTAGCTGGGA?73560

CTACAGGCAC?CCGCCACCAC?GCCCAGCTAA?TTTTTTGTAC?TTTTAGTAGA?GACAGGGTTT?73620

CATCGTGTTA?GCGAGGATGG?TCTCGATCTC?CTGACTTCGT?GATCCGCCCG?CCTCGGCCTC?73680

CCAAAGTGCT?GGGATTACAG?GCATAAGCCA?CCACGCCTGG?CTAGTAAAAT?AGTTTAAAAC?73740

ACACAGAGAC?AGCACAGGTA?GCTTGGCAAA?CAAGGTCATA?TGAATGAGAA?TGCAAGGCTT?73800

GTCGGAGAGG?CTATGGGCAG?GAAAAGGAAT?CACAGTGGGA?TGGATAATCA?AGGAAGGCCC?73860

ACTAGAAAAA?GTAACATTTA?GACCAGGCGT?TATTTCAAAG?GGTGGAGCCG?TTGTAGGGCA?73920

CAAATAGAGA?ATGGTAAAAC?TTGGGGGGAG?GTGGTGGAGA?ATGGTCACAA?GCTAGGAAAT?73980

TTGTAAGCAA?AAAGGATGTG?TGAGGCAGCT?GGGTTCAAGT?GGAACCAGGG?CATGAGGGAT?74040

GTGAAGGGTG?GAATAGATGA?TGGGCAAGAG?GTTTGGCTTC?ATCTGTGCAC?GTAGTCATCA?74100

AACTGGTCCT?GTGTCCCATC?AGCACAAGGC?ACTCTCTTAG?GAGCCAAGGG?ACACTGAGGC?74160

AGCCCCCATG?CTCAAAGAGA?AAGGGAAGGC?CATGTGATGA?TCTAGGATTC?ATAAAATCCA?74220

TGGAAGGCTT?TCTAACAGAG?GCCAGCTATT?CAAAATGCCA?TCTGGGGGGA?GATTTAACTG?74280

AGGGCAATGC?CTGTGTTATT?GACAGAGAAA?GAACAAAGGG?TGTCCATAAG?CAGAGACCAA?74340

TTAGGTGATT?TTTACAGATG?ACAAATATAA?GAGTTCAGGT?TTGTGTTACG?GTAGCATAAT?74400

TCAAGGGCAA?AAATAAAACC?AAATGGTTAT?AGATTTTGCG?TAACTTTTCT?GATGGATAAC?74460

TTAAGATTTG?ATGCAACAGG?AATCACCATG?AGATATGAGT?TGCAATGGAA?AGTTTTTATG?74520

TTTTTTTTTC?TTGCCAAGTA?TAGTTCAGAT?GTCAAAGGCA?AAGAAAAAAA?AGTCAGAAAA?74580

TAAAATTATT?TGGAAACATC?AGAAACTGCT?TGTAAGGACT?GGTTATTGTG?GCTACTGTTA?74640

ATTAAGAGCA?TTAATAACTG?ACAGGGACCC?ATAATTCTGG?AAGACAAAAG?TAACTAAGTC?74700

ACAAAAAGCT?GCCTTATGAT?ATTAAAATAA?AGGAGCAAAT?CAATGAAAAA?GCCTACAGTG?74760

GCACTCTCAG?AAAAGTCTAA?AACAAATGTT?GAGCAATTCA?AGAGAAATTT?ATTGGGTCTT?74820

CACTGAGCAT?CAGACAAATA?AGTTCCTCAA?GACAAAAGAG?GATTAAAAAA?TGTTGAAGAG?74880

TAAAACCACT?TCCTGAAAAC?CTGTCATCGA?ATCATTAATT?TATTGGGTAC?CTACTTTGTA?74940

TAGAGCAGAG?TGCTACCTAT?TTTAAGAAAT?GCTGTGGTAT?AATAGCTCCA?GAATGAATTA?75000

GGGCCTACAT?ATGTCAAGGC?AATCTGTGAG?TAAATGCCTA?ATGAGGTAAA?CATGATTAAT?75060

GCAGTGAGTT?CGATATAGAA?ATGGGTCCTT?GGGGCCGGAC?ACGATGGCTC?GTGCCTGTAA?75120

TCCCAGCACT?TTGGGAGGCC?GAGGCGGGCG?GATCACGAGG?TCAGGAGTTT?GAGACCAGCC?75180

TGACCAACAT?GGTGAAACCG?TGTCTCTACT?AAAAATACAA?CAACAACAAA?ATTAGTCAAG?75240

TGTGTTGGTG?CACACCTGTA?ATCCCAGCTA?CTCAGGAGGC?TGAAGCAGGA?GAATCGCTTG?75300

AACCCAGGAG?GCAGAGGTTG?CAGCGAGCCG?AGATTGCGCC?ACTGTACACC?AGCCTGGGCA?75360

ACAGAGCGAG?ATTCCATCTC?AAAAAAAAAA?AAAAAACAAG?AAAGAAAAAA?GAAATGGGTC?75420

CTTGGGTTCT?ACAGTTCACC?ATGGTCAAGG?GATGGACAAT?CAGTGGACAA?AAGACTCATG?75480

AAGGATGACT?GGGGAAACAG?ACTGGTTAAA?AACTGACTCA?TTTAGTTGAC?TTGCTACCAG?75540

TGCCTTCTGT?CTTCTGCTAG?CTTTAGTTAA?AACGGCTTAG?GAAGAGTCAA?AAGACTCTCA?75600

TAAAACTAAG?CCAACTCTTC?CTTGAATTCT?CCTCTTCTTT?ATTGACAGAA?ACAAGCCTGA?75660

TGTGATCCAC?TAAAACCACT?GCAGATCATT?TGGCTACTCT?TTGGAACATG?CTTTAATGCT?75720

ATTACAGCAG?TGTTTTTCAA?ACTGCTATGT?GTACAGGAAT?CACCTGGGGA?CCTTGTGAAA?75780

GTGTACATTC?TGTTGCAGTA?GGTCTGGGGA?GAGGACCCAC?AATCCTCATT?TCCAATAAAT?75840

TCTCAGTGAT?GCCAGACCTC?CTGTAAGCGG?CAAGGTATTA?GAACATCTTC?AGTTGCTGTT?75900

ATCAGAAGAT?GATAGGAAAC?CATCATTTTC?GGGGTCAGAA?TGCTGGAGCT?CAAGCTTTGG?75960

GCCTTGATGC?ATATAATAAC?TCATAAAATG?TAATATTCAG?GAAGGAATGA?GGCTCCTAAA?76020

GAAGTGAGAA?AGTAGAATGA?ACAAAGGCCT?AAGAGAATAG?AAATGTATTC?TAACAATATA?76080

AATTATAAAA?ATAAAAGTAA?GAGTGCCCAG?GGGTATTGAG?ATTGTTAGAT?TATTTTATAA?76140

TGATATAACT?TAAGGGATTC?CAAAATAATG?AACATAAAAT?GTTATTATTA?GATTTTTTTC?76200

CTTTTCACAT?ACTTGAAGGA?CAAATTATAT?CATATTGTCT?TTTTTTCTTC?CCCAATACTA?76260

TGAGCGTTAG?AGAATGAGAC?GCAAATCCGA?TATGTAGTAA?CAAGGTAGTC?ACTCACAGCA?76320

AAAGTTGAAA?GATTCCTAGT?CTACGCTAAC?AAGTGTCTGC?AAACTCTACA?GAAATGCAAT?76380

TAGAGGTTGC?GGCAGCTACT?CCCCTGCCTA?AAACAGCAGT?CTGAAAACTG?CCAATCTGTT?76440

GCAAATTCTG?TCTTTTCTGA?GAATATTTTA?AGAAAAGTGG?TAGAGAAATA?TTTGAAAGGC?76500

AACAGAACAC?TAATTATATC?TAGACAAGTT?TCCTTTTTTT?TTTTTCCCAA?AAAATATGAA?76560

AGTTCCTTTA?GGCTTTACAT?CTCCTAGGCA?TAGCAAAGCA?TTTCATAACT?TTCTACCTTA?76620

GGAAAAATTT?TCACAGACAT?TTTAACCAAT?TCAGAGGAAG?GGGAGAATGA?AAATACCATA?76680

ATTAACCAAA?GAGGAATAAT?ATTACCACCA?AAACCAAGTA?AGCCTTTTAT?TTAGGAAGGA?76740

GTGAGCTCTA?GCTGAAGTAA?ACATGCTATT?TAGTCAGGAT?GTATGCTCAG?ACACCTGTAG?76800

TCGGAAATTT?TCAAAATAGC?TATGGTTTTT?TTTCTTCTCT?TTTTTTAATA?GTAGTCATCT?76860

CCAATGAACA?CCAGTGGAAG?TCTGTGGTAT?TTCTCAGTTC?TGACCTGTCA?TGACTTTTGT?76920

TAGTTTTCTA?TTTTGATTAG?CTAAAGATTT?TCTAACTCAA?CTTCAATGAT?TTATTCTACT?76980

AACAAAATAG?TACAGGGATA?ACAAAGAATG?AAATGTTTCA?GAAGAGAAAA?TACTGGAAAT?77040

CTTATTTAGT?CCAATTCTTG?TCACTGTATA?GAAGGAAAAT?GAGCCCCAGT?GGGAAGAAAG?77100

ACAGCCTGGT?CACCCAGACA?CCTAGATTCC?TGGTACAACA?TACCTTAGTC?TTTACCAGCT?77160

GTCTCCTAGG?TAGAGTCCTT?CTAATCTCAA?ACTAAGGGTC?AGAGCTAGGT?TATCTTTCAT?77220

CCAAGATGAA?GGTTTGTGAT?AATTACATCT?TTGCAACTTC?TTTTCTACTT?GGCATGGGGC?77280

TCTAAAGTAG?GAAAATGATG?AAGGGTTTAG?CTAAACCTGG?AGGAAAAATA?TTTTGGTTTT?77340

GTGAAATAAC?AATGCAGATT?TCAGTCTCTG?TTTGCAATGG?GGGGAAGGAG?GAAGAGGCAT?77400

TTTTTAACAT?TTATTTTCTA?AACCAACAAA?CAAATCCTAC?CATTAGTCAA?AGACTCAGGT?77460

CTTTGGAATC?TGAAGCTTGT?AAATTTCAGG?GGCACTCTTT?AAGAAGAAGA?ATACAAAATT?77520

AAGAATAAAG?TGAATATAAA?ATTAAGAATA?AAGTGAATAT?TTATTTAGAA?TTAAAATGGC?77580

ATACAGGCCG?GGTGCAGTGG?CTTACACCTG?TAATCCTAAC?ACTTTGGGAG?GCAGAGGTGG?77640

ACAGGTTCCT?CTGAGCCCCA?GTGTTCAAGA?CCAGACTTGG?TACATAGTAA?GACACCATCT?77700

CTACAAAAAT?TAAAAAACAA?CAAAAAACAA?AAAACTGGCC?GGTCTTGGTG?GTGCATGCCT?77760

TTAGTCCGAG?CTACTCTAGA?GGACTGCTTG?AACCTAGGAC?TCCAAGGCTG?CAGTGAGTTA?77820

TGATTATGCA?ACTGCTTTCC?AGACTGAGTG?ACAGAATGAG?ATCTCATCTC?TGGAAAAAAA?77880

ATTTTAAATA?GTATCATACA?AACAACAAAT?TTTTAAAAGC?TATAAATACT?ACAAATATGA?77940

AGTGTTTAAA?AAACAAATAT?TTTTATTAAC?TGATTGCCAT?ACCTCTGAAA?TAATTCTCCT?78000

ATATTTTTTG?GTTGCACACT?CTTTGATCAT?CTCTTCCAAT?AACATTTTGC?AATATTCTCT?78060

ATTGAGAGAA?TAGAAAAATA?ATTCAGTCTT?CCCTTTAGAA?ATGTAGATCA?GAATTTGTAA?78120

TTTATTCTTG?AATAATTTGG?AAAAGTTCCT?TTCAGCTTCA?TAATTCATTA?CAGGTAATGT?78180

CATATAAATT?TTTTGGATTG?ACTTCAAATT?TGGAAAACTT?TTATCAGGTT?TCTTTTATAT?78240

GTGAGCTGTA?AGATTCAGGG?CACTGCAAGA?TTTCGTAGTA?TTTGACTTGA?TGACACTTGT?78300

TAACCACATT?GCCAGGGCCT?CTCCTAGAGC?CAGGAGATGG?ACCTATACCA?GGGTATAGGT?78360

AGCCTTGAAG?GTTAAGTTCA?AGCACTTCAC?AGTAAATCCA?CCTGAGCCTG?GCATTTATAT?78420

CCTCAACATA?TTTGATGCAT?CTGTGAAGTC?TCCCAGTCCT?TTCAAATAAA?GTGCCTGTTT?78480

TACTCAGAAT?ACCTAAACTT?CCTGATGGCA?TAATTGTTCC?ATGATTCAGC?CAAGACTGTA?78540

TCACTTGAGG?TATACACTTC?ATTTTTCCAT?TGAGATCACA?AGACAGGCAT?GATGTTTGAC?78600

TACCTGGTGT?ATAAACCGAG?TGTTATTTTA?TTACACTAAG?AAAATGCAAT?GGGATAATAT?78660

ATGAAGAATG?CTAAAACACT?AGAAAAATGT?TGGATATTAT?TATTTCTCTT?AACCTCTAGT?78720

CTTCCAACAC?CCATGCTATA?ATGGACAAGT?AGTTTATGTC?AATTAAGGCA?GACTAGTCTC?78780

AGTACAGTAT?AACAATTAGG?AATCTAGATC?CCCAAACCAG?ACCATCTTGG?TTCCAACCCC?78840

AGCCTAATCA?TTTTCTAACT?AGGTGGACTT?AGGCAAATTT?ATTGACTCTG?GAGGATTTAT?78900

AATAAGCATA?ATATAACCTA?CCTTCTAAAG?TTGTTTTGAG?GGTTAATACA?CCTGAAGTAC?78960

TCAGCATGAT?CCGTGCAGTA?GCAAGACCTC?AATAAGTGGT?AGCTACTATG?ATTATTGGGA?79020

AATTAGTCCA?TGAAGTCTCT?TGAGAAAAGC?TACAGGGGAA?ATAAGCCCAA?TTTCATTTCC?79080

CTATGTAGAA?AAGTTTGCAG?GATTTGGGCG?TGACAGGTAG?TCATCCACAA?AGCAGCAGTG?79140

TTATCGCCCC?ATAGGAAATG?AAGACTTCGT?AATGATTTAT?ACTTTAATAA?AGAGCTGCTG?79200

CAGCATATAC?TGAAAATATG?CACCCAACCC?ATATCTTCTT?TCAAAGGCAT?TCATGTTGGT?79260

TCAACCAAAT?CCCTAGTTCT?CTAAAATGAA?GTTTTGACAA?TCTTATATCT?TCTAAAGCAC?79320

TGAGAAGCCT?TTTTCCTTGT?TTTCTTTAAA?GAGGCTTGAG?AAGAACCAAG?CCTTTTTTTG?79380

GTTCAAATAA?AATATTTACA?ATAGGAGGAA?AAAACATTCA?GATAAACTTC?ACCTTGCCCG?79440

CCTGGTGGTC?TCTCAATACA?CAGAAGAAAT?GCAACTAGGG?CACTAGGAAA?TCTAAAAAAA?79500

AAAAAAAAAA?AAGGAAAGAA?AAAAAGTATA?GAGCTAAAGT?TCACTTCAGG?ACAACGCAAA?79560

CTAAGAAAAA?CTACATTTCC?CAAAGGAAAT?AGAGCACTAT?GTCTACAAAG?TAACTCATTT?79620

TTTCTTTAAT?GTTCAATGTT?GTCTATTCCA?GGGAAAAAAT?GGTACAATTA?ACCAAAACTT?79680

ATTTCTACCC?AACATCTCTG?CAAAGGAATG?TTGCTGCTGC?AGATCCACCC?CCAACATGGG?79740

AAGGCCCAAG?GCAAGTGAGC?AAATAGAGGC?CCATGTACCA?TAAGTCAAAA?CATTTAAAGT?79800

TACAAATCAA?GCTAGCAAAC?TGCTCAATAA?AATAGGTGTT?ATCCTTCTAC?CTAGACTGAC?79860

AAATATATCT?TTTCAATGTC?TTGGAAGACC?AGGTACAACT?TTAGAACTCC?TACAATGTTC?79920

ATAGTCCTTC?CACAGAAATG?GGTGGTTTAA?AGAGAGACAT?CATCCTGAGC?CCTGGTAATC?79980

AATTTGCCTT?CCTCCCCCCT?GCCTGCTCCA?TCCTACATCA?AGAGGGGCCT?TGTGATATGT?80040

GGACACCCAA?GCTCGCTCTC?TGTCTCTCTC?TCTCTTTCTC?TCTCTCTCTC?TCTCTCTCTC?80100

TCACATACAG?ACACACACAC?ACACAGAGCT?ATCCCTTAAA?CAACCCTCGT?GCAGAGATTG?80160

CACAACCAGT?AGCAATGACA?GCCTTCAGGA?AGATGGCTTC?AAGGATCCAT?GCAAACTGCA?80220

GATACCAGTT?CAGGGCCTTC?TGGACAGCGA?ATGTGGGTTC?CCACATAACC?AAATCATGGT?80280

CTAAAAATGA?AAAGAGAGTA?AGACTGGAAG?GCCCAAAAGT?CACCTCACCC?CATAGGCATG?80340

GCTCTGACCA?GAGAAGAATG?ACAGCAGAGT?ACCATCTAAG?GCCCAGGACA?GAGGCCAGTT?80400

GTGTTCATAT?ACTAGGTCTA?TATTTTAGTT?GTAGAGCTGA?AAAAAATTGG?AGGAAAATAT?80460

TCCCTCAGAA?AAGAGAAGAA?AAAAAAAAAA?AAAAAAGAGC?TGCATGTCTT?GACCTTTCCC?80520

AGATAGAATC?TCCCCAGTCA?TAGGTACGGG?CCCTGAAGCT?AAATCTCATC?TAATAATGAT?80580

AGCTTCAAAC?CTACAAACAA?AACACAGATG?CTAGGGAACC?CTTAAGAGTC?TAAGCAGGAG?80640

GCCATAAGTA?GACTAAACTG?ACTACACCCA?AGAGGATAGT?TGCTACTTGT?TGGGTGCTAA?80700

GACCTAGAAA?GCTGACTGTG?GCAAGTAAAA?GGCAGAAGTA?CTCCTGATGT?AATGGGTGAG?80760

GAAGAGAATC?TTAACCTCCT?ATAAGTTTTC?AAATTGTCCC?CTTCAAAAGT?CAAACTGTCC?80820

CCTTCTTCTT?TGTTATGTTG?GATAAAGTCG?GCTCTTCTTG?CCCTCATCAG?CAGTTGTACA?80880

CGATTGTACA?CAAATGATTG?TCCTACACAC?TCAAAATTTG?GGGTTTACAA?TACACATCTT?80940

TGCAAATGGG?GTATGTCCAA?CTGCTATAAG?TGGCCAAACC?ACAGGTCACC?CACCATGAGT?81000

CCTACCACTA?AGACACCATT?GTCAAACTGT?GGGCTGTAGA?GTTTCCTTAT?GCAAAGAAAC?81060

TCTGCCTTAT?CTTGATTTTC?TGTGGTACAA?ATGTAGTCAG?GAAGGAGGCA?GATAATGCAA?81120

GCAAACCAAA?TCAATTAAAT?CAGGAGCACT?GAACTGATGA?CATTAGATGG?TAAGCTTCCC?81180

CTCTCTCAAA?TCTGATATCC?ATTCACCCCT?CTTCAGCCTC?CCTCCCAACA?CACGCATACA?81240

CACATAGAGA?CCACACGAAA?GAACCTAGCA?GCATGCAAGC?ACAAGAAGCT?TGGGCCACAC?81300

ACTCATACAT?GCACCCAGGC?AAAACTCCAG?AGAGACCCTG?AGCAGGATCC?ATCTTTCCAT?81360

CCATAAAATA?AAGATAATAA?AACTTATCTT?GGAGATTTCT?TCCTAGGATT?AAATGAGATA?81420

CATAATATCA?AGTGGCTGTC?TCAGGGTAGG?TTCTCAAATG?TTAATTGTCT?TTCTCTTCCT?81480

TCTCCCTGAG?ATGAGACAAT?TTGCCTGTCC?AGCATTCCAA?ACCCTTTGGC?ATGCCAAGCA?81540

AAGAAGTATG?AGTCATTATC?TTGCCTCAGT?CACAAGCAAC?AAGTACCTGT?GGAGCAAAAT?81600

ATTACCAGGA?AAGTAGAGAG?TGCAAAAGAA?GCGGTGAGCA?TTCTTGCTGC?GAATGCATAT?81660

CTGTTCTACT?GAAAATCATA?ACTTAAATCT?GCTGAAGTTG?TACATAAGGA?CCTGGAGGGT?81720

AGAAGCTAAC?AAGGTAACAG?AGTTATGCTT?TTATGTGGAA?CTTGGCCAAA?TAATGCCATG?81780

CTGTAGCCAG?GAAGTATGTT?TCCCCTGCAC?CCTATTTAAA?ACTGCTTTGG?TGGTTTGCAT?81840

CAGACCTAAA?TAATATCCAC?GCTACTCTAG?AGTAGGCAGT?GGTGGCTACA?AGACCACACT?81900

TCCCTTCAAC?CAACGCTGCT?TCACCCTTAT?AAACCAAAAC?ATAAAACCCA?ATGAAAAAAG?81960

AAACTTAAAA?AATAAATTTA?GATTTTAGCA?CTTCATTCGT?AATAAAATTC?TCTTTCCGAC?82020

ACCCTTCTAT?GAAAAAAAAA?AAAAAGAGGA?ATCAGTATCT?ACTGGATAAT?TCCTCTGGTG?82080

ACTTTATTTA?AAATTTTGCA?GTGGCTTTCA?AGGCCCTACA?CTGATTCAAA?ATTTATGGCT?82140

AAAGGAATTG?CATGAAAACT?TCTAGCAGCT?TTCCATCATG?TTTGTCAGAA?GTTGAAACAT?82200

CTTTTTCCAT?ATTTCATGAG?AATACAAGAA?CCAATTCCAT?ACTTCAAAAA?CAGTCAAATT?82260

ACTTATTGTG?ATCAGAACTA?AAACTATTCT?AACTGAAAGT?AAAGATTTTA?CTATTTGGAC?82320

CAAACACCTA?ACAAACAGTG?ACTGCTTAGT?TAAATGCTCG?ACCTCAGTTG?CATTAGATAC?82380

AGTAGGATGA?AGTGGAGGCT?CAGCTCAGCA?CTTCCTGGGT?GCTAAATGAT?GTGTCAGGCA?82440

CTGCCAGAGA?TCCCAGAGAT?AGAAAACTGA?ATAAGATTGA?GAGGATTAAA?GGTATAATGG?82500

GCAAGAGAGT?TACGTAAAGA?TATGACTTTG?GCTTGGTATT?GTTACCAGCT?AAGTGAGAGG?82560

TCTGTATCTC?ATAGGAGACA?TTTACCTCAA?ACTGGGACAT?TCAAAGCAGG?TTTCCTCAAG?82620

AAGATGACAC?TTGAACTACG?TCTTAAAAGA?TGAGTGAAAA?TTAGCCAGGT?AGCAGGAGTT?82680

CCAGACATCC?TGAACAAAGG?AACAGCTGCC?TAAATTGCTC?ACATTGTGTG?TATGTGTAGT?82740

GACACAAATA?GACTGGGAAA?ATGTGGGCTG?TGGTGGGATG?TGAAGCAGCA?GAGTCAAATG?82800

GGAACCAGGT?CAGAGGCCCC?TGGTAAGCCC?AATTAAGGAG?TTAATAGTAA?TAACAGAAGC?82860

TGATATTTAT?TGAGCATTTA?CTATGTTGCA?GGCACCATGT?TAAATACTTT?AAAACAATAT?82920

TTTATTTAAT?CCTCACCATA?ACTCCATAAT?CCTCATTTTA?CAAATGAGAC?CAGGGATGAC?82980

TAGTAGGTAA?AGCAACTACA?ACAGGCTACA?CAGCCAGTAC?ATGGCAAGTG?GGTCTGGAAC?83040

CCAGGACGGC?CTGATTCCAA?AGTTTATACC?CTACACTCTT?CTACCACCAG?CCTATCCTCA?83100

AAGAGAGCAC?TAAATGAACG?CATTGGGTCC?ATCATGCTGG?CTATGGAATG?GAGAATGCAA?83160

TTAAAGGCTG?CCCAACTGGG?GCTCCGTGAC?AAGGCAGGGA?TAGGAAAGAG?ACAACAAATT?83220

GATTCAAAAA?TACATTCAAT?GGGACCTAGA?AGGAAACATT?CAACATGCAC?ATCCTCCTAG?83280

TGCATACAAC?AACAAAAAAA?AATGAGGCTT?TTGAAAATGA?GGTGTAGAAA?ATAAAACACC?83340

AGTATTCCAT?AATGCTTTCA?AATATAAACA?GTTAAAACAC?GTATCCTTTT?CTTTACTTAT?83400

AACATGCTCC?CAGCTGTTAA?ATTCAATGGC?AAAGACCAGG?TCTGTCTTAT?TCATCTGAGA?83460

TGGTATCCCA?GGTCTGAGCA?TCCTGCCTGG?CAAGAGATAC?TCAATAAATA?TGGTTGAAAA?83520

GGTAGAAGAA?AAAATGCCCA?GTTTTTGCAA?TGATATCAGA?GGTGCCTTAT?TGATCCAGAG?83580

TTAAAAACTA?ACCTTACTGA?AAAAATTAAA?AAGTCATGTT?CATAACTGAG?TAGAAAACAT?83640

GTAGTAGTTA?TGTTGACTAC?ATAGACAACA?GTCATCATTA?GGGAATGCTA?CATTGAAAAG?83700

AAGGCAATGA?GTTCAAAATG?TGATTAGTAT?TTTGTATAAA?TCATAACTCA?TTAAAAATAA?83760

GATGTTGAGT?GGCCTAAAGG?TGGAAATGTG?TTTTTATGAG?GCGGAAAAAA?AGCACGAGTA?83820

GACTGAAGAT?CAGATTTGGG?GCCTAATGAT?GTCTAGTCTC?TTACCCTGAC?AAAATAAGCA?83880

GGTTATTAAA?GTGATGTGAA?GAACCTGATC?ACTATGACAC?TTTTACAAAT?TCTTTGTCCT?83940

CAATAAGAAT?CTATCTACTT?CCAGGAACCT?GAAAAGTCAT?ATTTTTCAGA?CCTGAAGAGT?84000

TATTGTGCAC?TTTACAGTTT?TCCCCAAAAG?AGTCATTTCT?TAATTTTGAT?CATTTAGGAA?84060

GAGTGAATCT?ATTAAGTCAA?AAACGAAGAA?AAAAAAACTT?TCTATTTCTT?AGTGAAATTT?84120

GTTCTTTTAT?TTAAATCCTT?TGCATACTAC?TAAACAGAAG?TACAGAAGCT?ACTAAACAGA?84180

AGACAGATTT?TTGGGCCTTT?TTAGGTGACG?TAAAAGGAGC?TTGTTGTTTA?TTAAACAATC?84240

TCATTACCTG?ATATATTATC?TTGCATTAAG?ATATTTTGAA?AAAATGTTTT?CAGTTTACCA?84300

ATTACGTTAG?AGAAATTCTG?AAACTATTTA?CTTACATGAA?AAATTAAAAT?GTAAGTAGAA?84360

TTAGGTTTCT?CGTCTTCAAT?ATATCTGTCT?TCAACCATTG?GCCAACTTTG?AAAATTTAAT?84420

TTGAATCAAA?TGAATACAAA?TTCAAAATGA?TTCATTAATT?CAACCATTTT?GAAACTTCAG?84480

TTCTATAAAA?ATATGAAATC?TGTGGGCCTT?GTAAAACTGT?CTAAATACCC?AAATAAAAAG?84540

CCACCACGTT?TTTAAGCTAA?TTGTTTAAAA?GTGTGTATAT?TGATGAAATG?AAAGTGACTC?84600

GTGAACTATT?GGGTCTGGAA?TTTGCAAATC?ATAAACCTTA?TCCTTGTAAA?CAGAACCTAA?84660

CTAACAACAT?CAGGGCCTGC?TAATTTCCTT?CTTTTATAAT?CTGGAACAAA?AGTTGTAATG?84720

ATTTTTAACA?TCCACAGAAA?ATTAAGGGTG?CCATTTTAAA?TATTTATTAG?CAAAATGTCA?84780

CTTAGGTTTT?AAAAGTCTGG?AGGAAAATGA?GAGACAATTG?AACATTCTGG?TACTGCAATG?84840

CAGGAAAAAC?GCCAAGAACG?AAACACTAAG?ATTTTATTAA?AACCATAGGA?CTCAAATGTG?84900

TGTCAAGACT?TTTTGCTTGC?AATAGTGCCT?CTTCCTAATT?TGATTAAAAG?CTTCCATCTC?84960

CATGCCACCT?TCAATGTATG?CCATAATTTT?TAAAAAGTTC?CCAATCCACT?TCAAACACTC?85020

TAAAATTTAC?AACTGACCGT?GATGCGCATT?TTTTCTAGAC?AAACCTAAAG?GTAAATCTGC?85080

CCATGTCCCT?GGATAAATAA?AATGAGTGCC?TCCGGGTGAT?GTGGACTGTC?AACTCCTCTA?85140

CATTTCATCC?AAAGTCTACA?TGGGTCATCT?CCAAGTCACC?AGAAGAGCCA?GGGGAAAGGA?85200

GGGGAGGGGC?ACGATACGTA?AGATGTTAAA?CATGAAGATG?ATGTAAAATT?ACCCAGATTC?85260

AAGCTGGCCA?TTTTACAGAT?GAGGAAACTA?AGGCCCAGAA?AAAGCTCTAT?GACTTGCCCA?85320

AATACTCGGT?TACCCAGACC?ACAGCTGCAG?ATACTGTTAT?TTGGATCATA?GCTGCAAAAA?85380

GTCTAACTTT?TGGCCGGGCG?CGGTGGCTCA?CGCCTGTAAT?CCCAGCACTT?TGGGAGGCCA?85440

AGGTGGGCGG?ATCACGAGGT?CAAGAGATCG?AGACCACCCT?GGCCAATATG?GTGAAACCCC?85500

GTCTCTACTA?AAAATACAAA?AATTAGCTGG?GCGTGGTGGC?ACGCGCCTGT?AATCCCAGCT?85560

ACTCGGGAGG?CTAAGGCAGG?AGAATCGCTT?GAACCCAGAG?GCAAAGTTGC?AGTGAGCCGA?85620

GATTGCGCCA?CTGCACTCCA?GCCTGGTGAC?AGAGCGAGAC?TCCGTCTCCA?AAAAAAAAAA?85680

ATCTAACTTT?TGAAGTCTCA?GAGGTTTTAC?ACTTTCCATA?ACAAATAGTT?AAGAACCCCC?85740

ATTCCTGCAT?GCATATATAT?ATTAATATTA?TATATATTTA?TATATATAAT?TATATATATA?85800

TTTATATATA?TATAATATAT?ATATATATTT?TTTTATTTTT?ATTTTTTCCT?TAAAAACCTT?85860

CAGAGACAGC?GATCAGGTGG?GTAGCCTAGT?TAGGATTTTA?ACCCTTCGGT?TTCCAACAAA?85920

CGATAATTGC?ATAGAACCAT?CAACTCCCTG?AAGACAGGAC?TATCTTGTTC?CAGGCAAAAT?85980

CTACAGCCTC?TAGCACCCAG?TAGGCATTCA?GTGAGGGATT?CTCGGTTTCA?CCTGAGCATC?86040

TCCACTCCCT?ATCCATCCAT?GCCAAGGCGT?CAGTGGAGCC?AGCTAACTTT?CTTTTGGAAA?86100

TCGATTATTT?TCTTGAAACT?TGTTTCCAAA?AACTCCGGGC?CAAGAAGCCG?GCCTGAGGGA?86160

AAGCGTGGCC?GTCTCCAGGA?GCTAAGGACT?GAGGAGCTGG?CCTTTTGAAC?GGGTGGCTCA?86220

GAAAGAGCTG?GGTGGGCACG?CGGCATCGCC?ATGGGCGGAG?TGGCCCAGGT?GCGCTGGCTG?86280

CTTTGGCAGC?TCAGGCTGCC?GCTCCGGGCC?GCTGCTCCCC?GGCCGCCTTC?AGATAACCAA?86340

CTTCTCAAAC?TTCCCTTTCC?GGGGGTGGGG?GCTCGCCTCG?AACGCGGCCA?ACACAACGCC?86400

TTTCCTGCTC?GCACAAAGGG?GACCAAACGT?GCCCCGCGCC?CCTTGCAACT?GAACTTTCCT?86460

TCTCTTTTTC?AAGAAAAACT?CACAATCCCT?GCAGCTACGG?GAGTCGGGCT?GCGTGAGTGT?86520

CGCGGGGGAA?ACTTTCCTCG?TTTCCGCCCG?GGGGCCGGGT?TGCCGGGCCC?GACTGTCAAG?86580

CGCAGCGGAG?AGGCGGGGAC?CCCAGGAAGA?CCCCCGGCGC?CCCGCCGAGC?CCGGGCTGGG?86640

GACCACTCAC?CCGACTTCTG?AACGTGCGGT?GGGATCGTGC?TGGCGATACG?CGTCCACAGG?86700

ACGATGTGCA?GCGGCCACAG?GCCCCTGAGC?AGCCCCCGAC?CCATGGCAGA?CCCCGCTGCT?86760

CGTCATAGAC?CGAGCCCCCA?GCGCAGCGGA?CGGCGCCTTC?CCGGACCCCT?GGCTGCGCCT?86820

CCGCGCCGCG?CCCTCTCCGG?ACCCCGCGCC?GGGCCGGCAG?CGCAGATGTG?CGGGCCAGAT?86880

GTGGCGCCCG?CTCGCCAGCC?AGGAGGGGGC?CTGGAGGCCG?GCGAGGCGCG?GGGAGGCCCC?86940

CGGCGGCCGA?GGGAAGCTGC?ACAGGAGTCC?GGCTCCTGTC?CCGAGCGGGT?GCACGCGCGG?87000

GGGTGTCGTC?GCTCCGTGCG?CGCGAGTGAC?TCACTCAACT?TCAACTCAGC?GCTGCGGGGG?87060

AAACAGGAAA?CTCCTCGCCA?ACAGCTGGGC?AGGACCTCTC?TCCGCCCGAG?AGCCTTCTCC?87120

CTCTCCTCGA?CGTCCAGCCC?CTAGCTCTCT?CGTAGCTGCC?AATCATGTTT?CCTAGACCAG?87180

CCCCTCCGAG?AGCTTTGGCC?GACTTTCAGC?TGCCCCTCAC?CGCCCTCCCA?CACCACTCAG?87240

GAGTTCCTCG?CTCCAAGTAT?TTACTCAAGA?ATGACTAAGT?GCACACAGTT?CACAAAGTAA?87300

CAACAGAAAA?CGTCCACGTT?TTCCCTAGTA?GATCAGAACA?TCTGCCGCCT?CCCCTCAGCT?87360

TTCTTCAGAT?TGCTCCTAGG?TGCTTTAGAG?ATGCGTTTTC?AAATTGCAAG?TTGAGATCCA?87420

GGAGTGAATA?CTCCAATCTA?TTGAGTCGCG?AGCACATTTC?TTTCCCAAAT?AAAATAGTAA?87480

CGGTAAATTC?TACTTCATTA?AATTTGTGCT?TCAGTTGTGT?CTATATGCAT?GTATGTATGT?87540

GCATACACTG?TCAAGTTGTA?AAATGTTTTT?CTTTAGGTCG?AAGTCTAGAG?GTTTTTCTCA?87600

AGTTTTAATG?TACATATTGA?TCACCTGGAA?ATCTTATTTA?AAAATGCAGA?TTCTAATTCA?87660

GTAGGTCTAG?GAGGCAGGCA?GAGATTCTGC?ATTTCTAATG?AGCACCTGGA?TAGAGCGTCC?87720

CATTTTGCAC?CGCCTCTTCC?CGGGACTGAG?TCAGTGAGTA?ATTGTAAATG?ATCACCTATC?87780

ACGAAGTGAT?AGTGGTGGGA?AATGTAATTT?TCAGAATGTA?TAGAGTATAG?CAGAAACTGT?87840

AAAATTAAAA?GTGGGTTGGG?AGTCACCTGA?ATGCTTGTGC?TTTTATTCCC?TTAATGCAGG?87900

TGAAGAAAGA?GAATACTTAC?CCTCTCATGT?GCAAACGGGG?TAACATGGGA?GCAGAACAGC?87960

ATAAACTTTC?AAATTTCCTT?TCTTGCTAGG?GCAACCAGAT?TTGCCCAAGA?CATTCCTGGT?88020

GTACATGTTT?TGTAGTTTAA?ATATTAATAG?AACCCCCTTT?CTCTTTCAGA?TATGTCCTGA?88080

TTGGATAATA?AACTATGTGA?TCAACCTACT?TCCCACTCTC?AAAGATATGA?TTCTGTACAG?88140

CCCTCTGGTC?AGTAGATCTT?CTAGCAATTC?ATTTAATGAA?TTCCTTTACC?TGAGAGGAAG?88200

ATTGCAGAGG?CAAGGGTTTG?TGCCAGGGTC?TCCAGGGAAT?AAAGGTAAAT?AGCCCTCCCC?88260

CAAACCCAAC?TCCCAAATCT?TTCCTGTCAT?TCTAAGTGTT?CATTTGCTTC?ATCCTGGAAT?88320

TTTAACTCAT?GCTCCACCTA?GCACCCAAGC?TGCCTCTGGA?TGTTTTGCCA?CTTCCCAGTA?88380

CTCATGTTGA?AGATGCAGAA?AGTGCAGTGA?AATCAGGAGG?GCTAGGCATC?TTCTTTCCCA?88440

CCAATTAATT?GCCTTGCCAA?AGCTGGAGTG?ACTTTGTCAA?TGGAGGAAGA?TTGAGTTCCA?88500

AATCTTCTCC?CTATTCCCTC?TTCTGCCACC?AGCCCATGCC?ACTGCCATGG?CTTGTGTAGG?88560

AGTCTCCCAG?GAGTCACCCT?CAGCCACGGC?CGTTCTGGGC?TCTTTCACTC?AGTTTCTCAA?88620

ACGAGAGCTG?AATTCAGCTT?TTCAAAATAC?AAAACTAGTT?ATACCAACCC?TCTGATTAAA?88680

ATCATTTAAT?GGCTTCCCAC?TGCTCTTGAG?ATAAAGAGAA?GATAAAAACC?AGATCCTTGA?88740

ACGTGTCTTC?AAGCCTCCAA?CTCTCCCGTA?AACTTTCATT?TGGCTTCTCC?TTGCTTACTG?88800

AAAGCCTTCT?CCAAATTTCG?TGAATATGCC?TCTGTAATCC?TCCTACCCTT?TATGCTTAGA?88860

GCCTTCCCCA?GTGTGGACTT?CCTTCCTCTG?ACCTTTTTTT?CTTCACCCAG?CCAACTCCTG?88920

GTCTTCGTGG?ATTGAATCAT?AACTTCTTTG?ATGGGCAAGC?TTTCCCTCAC?CTCCATGAGT?88980

AGATCTTGTA?TTACACGTTC?TCTTGGCACC?ATAT 89014

<210>2

<211>4636

<212>DNA

＜213〉homo sapiens

<400>2

tttttttttt?ttttttctag?gaatgggaac?aggaggcagg?atgctcacct?gagtattttg 60

ctttattcaa?tctaataaac?attttattta?tgtaaaagac?aaacaatgca?tagaataaaa 120

ataagtgctt?gagacttttg?atataaaaag?agtatatagc?attcacattc?ctattttaat 180

acatgagtac?agctgaagtg?ttccataaaa?gaataaaact?ttccctttat?gtatagtagt 240

gaaaaaagtc?agtattttta?ggaactacag?aatgttattc?cttggtcttt?tttcttgaat 300

aagaaaaaaa?aacataaaca?aaacaagcca?cagtatcctc?tgacactaca?ttccagttta 360

tgctgataac?ccagaagtga?gaatactctt?gaatcttgaa?tatctcatga?atggaccagt 420

attctagaaa?ctcaccacta?gaggtcaatg?ggcaacagct?attgggatgg?tatcagcatg 480

ccctacggtg?caagtggaat?ttctaggcgc?ctctatgcta?ctgcagccac?actgtcttta 540

actctcagcc?cacccacact?gaggagggtg?cctagaggtt?ctatttccaa?acctttgcat 600

gtatcttaaa?aatctcaata?aaatgagacc?ttccaccatc?caaacagagc?tgatattctc 660

actaccagtc?cctctctaat?attcctattt?ggctgaaaat?aagtagcttc?aaaaagtttt 720

aaaaaagaga?ttacttgcag?cattaacact?tctttgttga?ttaacaagtt?tcctatggag 780

ttttaaagct?catactttgt?tcttgtcctt?gtggacacaa?attttctaac?tgcaaatggg 840

acctttgtgt?cccacattca?aatcctctct?agtaatttct?gcaaaggttg?agaaggctgg 900

catgatggag?agaacggtaa?ccatgaggaa?agcttcttgg?agtaaagcac?tcctctctcc 960

aatgcagagg?gtaaaactat?taacatataa?gcaaaagaaa?cttgggctaa?ctgagaccct?1020

taaaggagtt?cccctttagt?ccaataaaag?gccaacttca?aatcttaaca?ccagataagg?1080

tagtcaaaat?catattatat?acccagagaa?tgactgcttg?aatggacatt?tcttacaagg?1140

gaccttggtt?aggtgcagat?ttaattccta?gactgggtcc?aggtaggcag?tggaaagagc?1200

taatgtttac?agtgagaagt?gaggcagctt?tgtaagtgtc?tccacacctt?cacattttgt?1260

gaacgtggac?tggagataac?tgaaaaccat?ctgctatcct?tacctgggga?tccagatttt?1320

cctgcaaaat?ctccaaatat?ttataaagtg?gcttcacttt?ttgaaacgct?gtgctgacca?1380

aacaaaacat?atgtttagag?tgcctgaggt?catagtcctg?acaatgatag?tattgtgtag?1440

ttgaaatcct?cttcatcagg?ccaaactgtg?cttgagcaat?caggagccca?gaaagatgga?1500

acccattggt?gtttgtatag?aaaactagaa?aatcaagtca?agtgtaatga?aaaagtaaac?1560

acgataaagc?ctagagtgag?aatttgctcc?tttttagaaa?aggatgaagg?ctgggagcag?1620

agaatagtaa?cataagtgca?ggggaaagat?gaaaaaaaga?acaatttttc?attagtagat?1680

ggtggggcaa?tcgcatggat?ggggacatct?gttctgattt?ttctgcaacc?catgaaggta?1740

aaaagtgggg?ttcaaaacat?tcaaggtatt?aaagatgggg?tagagtttct?aaactaggtt?1800

gagggagagt?ttctaaacta?gccccccaga?tttggggctt?ggagcttaaa?tgaaaagtcc?1860

aggagaaata?agggcacaca?ggaaccccgg?gaacactggt?cctcaaacag?tgccactgta?1920

cttagttcca?tggccagaag?agaagtgcta?ggcagggaat?gattattttg?caaaagcaag?1980

tgcaatgtgg?tcatagctgg?ctgtgagaca?tggagcctct?ttcctcatgc?aaagttcact?2040

gttttacagt?cagagaacca?ctgcatgtgt?gattgtcaaa?tgctaatgct?gtcatgggtc?2100

ccttccttct?ctgcttggtt?ctggagttct?ccaataaaac?caatttcctg?ggaatatttg?2160

atgtttttcc?ttgtctcttt?tcaaggtatg?gctatatata?tagagctata?gacatatata?2220

gatatatata?tatatatata?aaacatagct?attcatattt?atatacaggc?attaataaag?2280

tgcaaatgtt?attggctatt?gtaaaaatca?atctcatttc?ctgaggaagt?gctaacacag?2340

cttatcctat?gacaatgtca?aaggcataga?atgctctatg?tcacccactc?cctgctgctg?2400

ttgtttctgc?ttatccccac?agcttacagg?gaggggagtg?acccccttgg?ttttccagga?2460

agcatcagtt?caggggcagc?ttcctgctgc?ctctgttctt?tggtgagagg?gcagcctctt?2520

tggacatggc?ccagcctgcc?ccagaagagc?tatttggtag?tgtttaggga?gccgtcttca?2580

ggaatcttct?cctccgagca?gctcctcccc?gagagcctgt?ccagatgctc?cagctcactg?2640

aagcgttctg?ccacacactg?ggctgtgaga?cgggcctctg?ggtcgtggtc?ccagcactca?2700

gtcaacgtct?cacacaccat?ctggatgccc?tggtggttga?gccagaagct?gggaatttct?2760

ggtcgccctc?gatctctcaa?cacgttgtcc?ttcatgcttt?cgacacaggg?gtgctcccgc?2820

accttggaac?caaatggagg?ctcataatct?tttacttctc?ccactgcatt?acagcgagat?2880

gtcatttccc?agagcaccag?agccatggag?tagacatcgg?tctgcttgaa?ggactcaaca?2940

ttctccaaat?tcatcctgga?ttctaggact?tctggagcca?tgtatcttgc?agttcccacc?3000

tgcccactgt?tagccaggtc?atccacagac?agagtagggt?ccagacgcag?ggaaagccca?3060

aagtcacaca?ggcagcaggt?taggtcgttc?ttcacgagga?tattggagct?cttgaggtcc?3120

ctgtgcacga?tgggcatctt?gggcctccca?catggagtgt?gatcactgtg?gaggtgagca?3180

atcccccggg?cgagggagct?gcccagcttg?cgcaggtcct?cccagctgat?gacatgccgc?3240

gtcaggtact?actgtaggtt?gcccttggcg?tggaaggcgg?tgatcagcca?gtattgtttc?3300

cccaactccg?tcttccgctc?ctcagccgtc?aggaactgga?gtatgttctc?atgcttcaga?3360

ttgatgtctg?agaagatgtc?cttctctgtc?ttccaagagg?catactcctc?atagggaaag?3420

atcttgactg?ccactgtctc?aaactgctct?gaagtgttct?gcttcagctt?ggccttatag?3480

acctcagcaa?agcgaccttt?ccccaccagg?gtgtccagct?caatgggcag?cagctctgtg?3540

ttgtggttga?tgttgttggc?acacgtggag?ctgatgtcag?agcggtcatc?ttccaggatg?3600

atggcacagt?gctcgctgaa?ctccatgagc?ttccgcgtct?tgccggtttc?ccaggttgaa?3660

ctcagcttct?gctgccggtt?aacgcggtag?cagtagaaga?tgatgatgac?agatatggca?3720

actcccagtg?gtggcaggag?gctgatgcct?gtcacttgaa?atatgactag?caacaagtca?3780

ggattgctgg?tgttatattc?ttctgagaag?atgatgttgt?cattgcactc?atcagagcta?3840

caggaacaca?tgaagaaagt?ctcaccaggc?tttttttttt?ccttcataat?gcactttgga?3900

gaagcagcat?cttccagaat?aaagtcatgg?taggggagct?tggggtcatg?gcaaactgtc?3960

tctagtgtta?tgttctcgtc?attctttctc?catacagcca?cacagacttc?ctgtggcttc?4020

tcacagatgg?aggtgatgct?gcagttgctc?atgcaggatt?tctggttgtc?acaggtggaa?4080

aatctcacat?cacaaaattt?acacagttgt?ggaaacttga?ctgcaccgtt?gttgtcagtg?4140

actatcatgt?cgttattaac?cgacttctga?acgtgcggtg?ggatcgtgct?ggcgatacgc?4200

gtccacagga?cgatgtgcag?cggccacagg?cccctgagca?gcccccgacc?catggcagac?4260

cccgctgctc?gtcatagacc?gagcccccag?cgcagcggac?ggcgccttcc?cggacccctg?4320

gctgcgcctc?cgcgccgcgc?cctctccgga?ccccgcgccg?ggccggcagc?gcagatgtgc?4380

gggccagatg?tggcgcccgc?tcgccagcca?ggagggggcc?tggaggccgg?cgaggcgcgg?4440

ggaggccccc?ggcggccgag?ggaagctgca?caggagtccg?gctcctgtcc?cgagcgggtg?4500

cacgcgcggg?ggtgtcgtcg?ctccgtgcgc?gcgagtgact?cactcaactt?caactcagcg?4560

ctgcggggga?aacaggaaac?tcctcgccaa?cagctgggca?ggacctctct?ccgcccgaga?4620

gccttctccc?tctcca 4636

<210>3

<211>16

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>3

cagcccccga?cccatg 16

<210>4

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>4

gctgatgcct?gtcacttgaa 20

<210>5

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>5

gccatggagt?agacatcggt 20

<210>6

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>6

gcaacagcta?ttgggatggt 20

<210>7

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>7

gtgcagggga?aagatgaaaa 20

<210>8

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>8

gtatcagcat?gccctacggt 20

<210>9

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>9

ggatccagat?tttcctgcaa 20

<210>10

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>10

ggagaagcag?catcttccag 20

<210>11

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>11

gagctcttga?ggtccctgtg 20

<210>12

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>12

gagaccttcc?accatccaaa 20

<210>13

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>13

tagctggctg?tgagacatgg 20

<210>14

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>14

ttttgaaacg?ctgtgctgac 20

<210>15

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>15

tcagccagta?ttgtttcccc 20

<210>16

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>16

tcacacaggc?agcaggttag 20

<210>17

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>17

tcaggaatct?tctcctccga 20

<210>18

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>18

tggtagtgtt?tagggagccg 20

<210>19

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>19

tatccccaca?gcttacaggg 20

<210>20

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>20

agcctctttc?ctcatgcaaa 20

<210>21

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>21

atgtcatttc?ccagagcacc 20

<210>22

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>22

aggaatcttc?tcctccgagc 20

<210>23

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>23

agccatggag?tagacatcgg 20

<210>24

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>24

atgctactgc?agccacactg 20

<210>25

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>25

ccttctctgc?ttggttctgg 20

<210>26

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>26

ccaggagaaa?taagggcaca 20

<210>27

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>27

cagcagctct?gtgttgtggt 20

<210>28

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>28

cccactgtta?gccaggtcat 20

<210>29

<211>24

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>29

cagcccccga?cccatggcag?accc 24

<210>30

<211>23

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>30

cagcccccga?cccatggcag?acc 23

<210>31

<211>22

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>31

cagcccccga?cccatggcag?ac 22

<210>32

<211>21

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>32

cagcccccga?cccatggcag?a 21

<210>33

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>33

cagcccccga?cccatggcag 20

<210>34

<211>19

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>34

cagcccccga?cccatggca 19

<210>35

<211>18

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>35

cagcccccga?cccatggc 18

<210>36

<211>17

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>36

cagcccccga?cccatgg 17

<210>37

<211>24

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>37

gcagcccccg?acccatggca?gacc 24

<210>38

<211>23

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>38

gcagcccccg?acccatggca?gac 23

<210>39

<211>22

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>39

gcagcccccg?acccatggca?ga 22

<210>40

<211>21

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>40

gcagcccccg?acccatggca?g 21

<210>41

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>41

gcagcccccg?acccatggca 20

<210>42

<211>19

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>42

gcagcccccg?acccatggc 19

<210>43

<211>18

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>43

gcagcccccg?acccatgg 18

<210>44

<211>17

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>44

gcagcccccg?acccatg 17

<210>45

<211>24

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>45

agcagccccc?gacccatggc?agac 24

<210>46

<211>23

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>46

agcagccccc?gacccatggc?aga 23

<210>47

<211>22

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>47

agcagccccc?gacccatggc?ag 22

<210>48

<211>21

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>48

agcagccccc?gacccatggc?a 21

<210>49

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>49

agcagccccc?gacccatggc 20

<210>50

<211>19

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>50

agcagccccc?gacccatgg 19

<210>51

<211>18

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>51

agcagccccc?gacccatg 18

<210>52

<211>24

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>52

gagcagcccc?cgacccatgg?caga 24

<210>53

<211>23

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>53

gagcagcccc?cgacccatgg?cag 23

<210>54

<211>22

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>54

gagcagcccc?cgacccatgg?ca 22

<210>55

<211>21

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>55

gagcagcccc?cgacccatgg?c 21

<210>56

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>56

gagcagcccc?cgacccatgg 20

<210>57

<211>19

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>57

gagcagcccc?cgacccatg 19

<210>58

<211>24

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>58

tgagcagccc?ccgacccatg?gcag 24

<210>59

<211>23

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>59

tgagcagccc?ccgacccatg?gca 23

<210>60

<211>22

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>60

tgagcagccc?ccgacccatg?gc 22

<210>61

<211>21

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>61

tgagcagccc?ccgacccatg?g 21

<210>62

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>62

tgagcagccc?ccgacccatg 20

<210>63

<211>24

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>63

ctgagcagcc?cccgacccat?ggca 24

<210>64

<211>23

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>64

ctgagcagcc?cccgacccat?ggc 23

<210>65

<211>22

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>65

ctgagcagcc?cccgacccat?gg 22

<210>66

<211>21

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>66

ctgagcagcc?cccgacccat?g 21

<210>67

<211>24

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>67

cctgagcagc?ccccgaccca?tggc 24

<210>68

<211>23

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>68

cctgagcagc?ccccgaccca?tgg 23

<210>69

<211>22

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>69

cctgagcagc?ccccgaccca?tg 22

<210>70

<211>24

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>70

ccctgagcag?cccccgaccc?atgg 24

<210>71

<211>23

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>71

ccctgagcag?cccccgaccc?atg 23

<210>72

<211>24

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>72

cccctgagca?gcccccgacc?catg 24

<210>73

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>73

atgtgaagat?gggcaagacc 20

<210>74

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>74

atctccatgt?gaagatgggc 20

<210>75

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>75

aacggcctat?ctcgaggaat 20

<210>76

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>76

aacatcgtcg?agcaatttcc 20

<210>77

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>77

aatccaactc?ctttgccctt 20

<210>78

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>78

aaacctgagc?cagaacctga 20

<210>79

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>79

agggcgatct?aatgaagggt 20

<210>80

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>80

agtgcacaga?aaggacccac 20

<210>81

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>81

acactggtcc?agcaatgaca 20

<210>82

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>82

ttcctgttga?ctgagttgcg 20

<210>83

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>83

cactctgtgg?tttggagcaa 20

<210>84

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>84

caaggccagg?tgatgacttt 20

<210>85

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>85

cacactggtc?cagcaatgac 20

<210>86

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>86

ctgacaccaa?ccagagctga 20

<210>87

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>87

ctctgccatc?tgtttgggat 20

<210>88

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>88

tcaaaaaggg?atccatgctc 20

<210>89

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>89

tgacaccaac?cagagctgag 20

<210>90

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>90

tgatgccttc?ctgttgactg 20

<210>91

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>91

ttcctgttga?ctgagttgcg 20

<210>92

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>92

ttctccaaat?cgacctttgc 20

<210>93

<211>20

<212>DNA

＜213〉artificial sequence antisense oligonucleotide

<400>93

ggagagttca?ggcaaagctg 20

<210>94

<211>1512

<212>DNA

＜213〉homo sapiens

<400>94

ttacattttg?atgccttcct?gttgactgag?ttgcgataat?gttttcttaa?tccgcaatgc 60

tgtaagccta?gctgctccat?tggcatacca?acattctctc?ataattttag?ccattactct 120

caaggcttca?cagctctgcc?atctgtttgg?gatatttggc?cttaacttct?gttcacaaac 180

aacttttctc?atttcttcaa?ctgatgggtc?agaaggtaca?agatcataat?aaggcagttg 240

gtaatcttca?tgaattccac?caatggaaca?tcgtcgagca?atttcccaga?atactaagcc 300

cattgcatag?atgtcagcac?gtttgaagga?ttcaaaatgt?ttcatattta?tggaatcatc 360

gagaacttca?ggggccatgt?acctttttgt?tcccactctg?tggtttggag?caatatcaat 420

ggtatctgtg?gctgaatcat?gtcttactgc?cagtcctaag?tctgcaatac?agcaagttcc 480

attcttcttt?accaagatat?tctttgattt?caaatctcta?tgagcaatgg?ctggctttcc 540

ttgggtacca?acaatctcca?tgtgaagatg?ggcaagaccg?ctcgccgtgg?acagagcaag 600

ttttatcatt?ccttccacag?taactgtgta?tctgtttaag?taatcaaaaa?gggatccatg 660

ctcatgataa?tctgacacca?accagagctg?agtccaagta?ccattgtctt?tattgtctgc 720

tgctataaat?cccaggatgt?tttcatgacg?taacattaca?gtttgataaa?tctctgcctc 780

acggaaccac?gaacgttctt?ctctagagga?gaatatctta?acagcaactt?cttctccccg 840

ccactttcct?ctccaaactt?ctccaaatcg?acctttgcca?atgctttctt?gtaacacaat 900

agttctcgca?attgttctct?gaacaagcaa?tggtaaacct?gagccagaac?ctgacgttgt 960

catatcataa?attaagtctt?tcaacgtagt?accctctgaa?ataaaagggc?gatctaatga?1020

agggtcctct?tcatttggca?ctcgatggtg?aatgacagtg?cggttgtggc?agatatagac?1080

catcaacatg?agtgagatgc?agacgaagca?cactggtcca?gcaatgacag?ctgccagttc?1140

cacaggacca?aggccaggtg?atgactttac?agtagttgga?agttctattt?tattgcaatg?1200

gtcctgattg?cagcaatatg?ttgtagtcac?agacccagtt?tttgaagagg?gtgcacatac?1260

aaacggccta?tctcgaggaa?ttaagtcaat?ttcagctata?cacatgctgt?tgtgtataac?1320

tttgtctgtg?gtctctgtga?cagagacaaa?gcagagccca?tctgtcacac?aagtaaaatt?1380

gtcttttgta?cagaggtggc?agaaacactg?taacgccgtc?gcccccggga?gcagcgccgc?1440

cgccgccgcc?gccgccgccg?ccagcacgag?gaggagcagc?cggggacgcg?gagcagcgac?1500

cgccgcctcc?at 1512

<210>95

<211>2308

<212>DNA

＜213〉homo sapiens

<400>95

aaacactata?ggttttaaca?tagagacttt?cagcaattct?actcatttcc?attagaaaga 60

cacagaagtg?gcacttactg?gtatagtaca?atcccatttt?gaaggcatgt?aatgttctga?120

ataagtgaaa?gaacaataat?agtatacaaa?atacaattgc?atgaattatg?ttcctcacta?180

ctatatgagg?tcatttttag?actcaagata?agagttttat?aagtgttagt?tttaagatcc?240

tgaaaaacta?tagaacagta?cattcaaagt?ctgaatcaag?gaaactctag?tggttcagaa?300

tcctctgaga?atgtactaac?caggagtaaa?tcactttctt?tagtaataag?acatgtttca?360

ttgtaattca?gcaatccaac?tcctttgccc?ttaaagatga?tctccagcac?agcagagtta?420

cctaaagtta?agaccagcaa?tcatcttttt?aaaaaacaag?ttttgttaat?aaaaaataaa?480

ggtagactac?acattttctg?tcctgggaaa?gaagcgttca?tagtgcacag?aaaggaccca 540

catggctgtt?tcctgggtcc?aaagaaatcc?tgggaagttt?ttaattgact?ttattacact 600

gctgcaaaag?gaagcaatat?ccttctgttc?cctctcagtg?aggtagaaca?attgacctcc 660

caaattaaaa?cccaggagca?gatctgaaga?aaaaaggaga?gttcaggcaa?agctgtagaa 720

ttacattttg?atgccttcct?gttgactgag?ttgcgataat?gttttcttaa?tccgcaatgc 780

tgtaagccta?gctgctccat?tggcatacca?acattctctc?ataattttag?ccattactct 840

caaggcttca?cagctctgcc?atctgtttgg?gatatttggc?cttaacttct?gttcacaaac 900

aacttttctc?atttcttcaa?ctgatgggtc?agaaggtaca?agatcataat?aaggcagttg 960

gtaatcttca?tgaattccac?caatggaaca?tcgtcgagca?atttcccaga?atactaagcc?1020

cattgcatag?atgtcagcac?gtttgaagga?ttcaaaatgt?ttcatattta?tggaatcatc?1080

gagaacttca?ggggccatgt?acctttttgt?tcccactctg?tggtttggag?caatatcaat?1140

ggtatctgtg?gctgaatcat?gtcttactgc?cagtcctaag?tctgcaatac?agcaagttcc?1200

attcttcttt?accaagatat?tctttgattt?caaatctcta?tgagcaatgg?ctggctttcc?1260

ttgggtacca?acaatctcca?tgtgaagatg?ggcaagaccg?ctcgccgtgg?acagagcaag?1320

ttttatcatt?ccttccacag?taactgtgta?tctgtttaag?taatcaaaaa?gggatccatg?1380

ctcatgataa?tctgacacca?accagagctg?agtccaagta?ccattgtctt?tattgtctgc?1440

tgctataaat?cccaggatgt?tttcatgacg?taacattaca?gtttgataaa?tctctgcctc?1500

acggaaccac?gaacgttctt?ctctagagga?gaatatctta?acagcaactt?cttctccccg?1560

ccactttcct?ctccaaactt?ctccaaatcg?acctttgcca?atgctttctt?gtaacacaat?1620

agttctcgca?attgttctct?gaacaagcaa?tggtaaacct?gagccagaac?ctgacgttgt?1680

catatcataa?attaagtctt?tcaacgtagt?accctctgaa?ataaaagggc?gatctaatga?1740

agggtcctct?tcatttggca?ctcgatggtg?aatgacagtg?cggttgtggc?agatatagac?1800

catcaacatg?agtgagatgc?agacgaagca?cactggtcca?gcaatgacag?ctgccagttc?1860

cacaggacca?aggccaggtg?atgactttac?agtagttgga?agttctattt?tattgcaatg?1920

gtcctgattg?cagcaatatg?ttgtagtcac?agacccagtt?tttgaagagg?gtgcacatac?1980

aaacggccta?tctcgaggaa?ttaagtcaat?ttcagctata?cacatgctgt?tgtgtataac?2040

tttgtctgtg?gtctctgtga?cagagacaaa?gcagagccca?tctgtcacac?aagtaaaatt?2100

gtcttttgta?cagaggtggc?agaaacactg?taacgccgtc?gcccccggga?gcagcgccgc?2160

cgccgccgcc?gccgccgccg?ccagcacgag?gaggagcagc?cggggacgcg?gagcagcgac?2220

cgccgcctcc?atggtcccgc?cgccaccgcc?tgtggcccgg?cccggcccgg?ccgcgccgct?2280

gcctcacccc?agcaaacctc?gcctcgcc 2308

<210>96

<211>48775

<212>DNA

＜213〉homo sapiens

<400>96

cctaggatgg?gcagtataaa?caactgtgtt?tttaaatgac?aaaattatta?ctctaatcaa 60

atttatctgc?agttatcgac?agtaatcatg?atccatccca?ccttttaagt?ttctttcatt?120

ttcaatatca?gccaattgtg?gtttatcaaa?ccatccctag?ccaaaaaagg?aattaactgc?180

agtaatacgt?aaagtcaatt?tagaactaaa?ctccaacttt?aaaaaaattc?cctgattcat?240

caaaagtaca?ttttatccac?ttaggtaaga?aaagtataat?tgtaactcaa?tctttgattc?300

aataaaaaat?atcttcagca?aaagtggata?accttacatg?aaagtgagaa?atcatgtatt 360

acaactttaa?atcagacaac?ttttggtata?ttcttaaaat?tatataaaaa?tagttttagt 420

gataaaatgc?attggtcccc?tggatttcat?aaagcagatc?tggtaggctt?agaaatggcc 480

caaaaacaac?aacaaaaaaa?aaaaaacaaa?aaaaaaaccc?ccacaaaaaa?agtacctgat 540

cacagaatta?gagattatta?ttaaacaagt?aatacaacac?aactataaaa?acaaacctct 600

caaactcatt?catttgcttc?aatgaaatta?tggtaactac?agaaaaaaac?tcaactttgt 660

agtcaaaata?gtaacctcta?agcatttttc?ccatgatgtt?tttaaacaca?tgaaattgac 720

actaaattcc?tatgtaatat?gtcactcatt?ctaaaattac?tttggtttta?agatcaaata 780

gtctttcaaa?tttattctac?gtataagaga?taagacatta?tcagaatgca?actcattcag 840

tgtaaatggc?cactttctct?tcctgaccaa?aatactgtat?gggttactct?gaccctgtat 900

cggggaactg?atagcactat?aaagtcgaag?tcttgcctca?gagctatgat?agttttttct 960

cccctcagaa?taagatcaca?gtgataaaag?gacttcgaaa?actgtaaaag?ccctgcagag?1020

acttcatagc?attggaagta?aaaaccagtt?attataagct?agtttcaact?taatgtaaga?1080

agaccatgac?aagtttgctt?tcaatatttg?accaaagaca?tctgtaaatg?gagaaaaacc?1140

tatactcaga?atgttcttta?gctaccacct?ctcccaagta?acaagggtgc?actgaatgca?1200

ttacataaat?tacatgtaag?cagttgcaat?gtacgcacac?ataaggaaac?actgaattaa?1260

aagctgcctt?cctcaaagtg?tagtgagacc?tcaaaaccac?actagctcta?acctcagtta?1320

caaagacaga?ggatccaccg?aacgtttact?cctacataca?taacaaatgt?gactttcttg?1380

cacatctgtt?atctattcaa?attattaact?accttcgcct?tcctagaaaa?aggcctatta?1440

tttaatatta?accatattct?aattttaaat?gtaattcatg?tcttaaaaaa?taagtctttg?1500

aacagataaa?gaaaaaaatg?gcttacagaa?taccacataa?cttttcacaa?gcagctagac?1560

agactttccc?ttttagaaaa?attagtctgt?atgctacaaa?tattaaagta?ctataagcat?1620

ctagagtgcc?acttgatttt?ttaaaagtat?acttagacaa?cacaattaaa?atgcaaaagc?1680

ttgatgtgag?aatattcaaa?catgaccatg?ctaataattt?actaattaat?gccacttcat?1740

ttctttagtg?gcttaagcac?attttggtag?gagaaaggca?ttttcagaat?agaataccaa?1800

atgacatacc?acaaaaaccc?ttccaaaaac?aaaacagaaa?aagtttgggt?tacccagata?1860

aataagcttt?ttgaattcaa?acactatagg?ttttaacata?gagactttca?gcaattctac?1920

tcatttccat?tagaaagaca?cagaagtggc?acttactggt?atagtacaat?cccattttga?1980

aggcatgtaa?tgttctgaat?aagtgaaaga?acaataatag?tatacaaaat?acaattgcat?2040

gaattatgtt?cctcactact?atatgaggtc?atttttagac?tcaagataag?agttttataa?2100

gtgttagttt?taagatcctg?aaaaactata?gaacagtaca?ttcaaagtct?gaatcaagga?2160

aactctagtg?gttcagaatc?ctctgagaat?gtactaacca?ggagtaaatc?actttcttta?2220

gtaataagac?atgtttcatt?gtaattcagc?aatccaactc?ctttgccctt?aaagatgatc?2280

tccagcacag?cagagttacc?taaagttaag?accagcaatc?atctttttaa?aaaacaagtt?2340

ttgttaataa?aaaataaagg?tagactacac?attttctgtc?ctgggaaaga?agcgttcata?2400

gtgcacagaa?aggacccaca?tggctgtttc?ctgggtccaa?agaaatcctg?ggaagttttt?2460

aattgacttt?attacactgc?tgcaaaagga?agcaatatcc?ttctgttccc?tctcagtgag?2520

gtagaacaat?tgacctccca?aattaaaacc?caggagcaga?tctgaagaaa?aaaggagagt?2580

tcaggcaaag?ctgtagaatt?acattttgat?gccttcctgt?tgactgagtt?gcgataatgt?2640

tttcttaatc?cgcaatgctg?taagcctagc?tgctccattg?gcataccaac?attctctcat?2700

aattttagcc?attactctca?aggcctacaa?gaaaatataa?aaaaaaaaat?taatgcatgc?2760

accattttcc?attggtctgg?ataagaattt?ttacgtgtaa?attttctttt?taaatgacat?2820

atacacttgt?tattgtttaa?gcattatttg?taatagcaaa?tgagtagaaa?ttacataaat?2880

ttccatcaat?agggtactgg?tgccagtgct?ggaaagcagg?tggacaaaga?gtgactcatt?2940

tagcaaacct?gaaaaggccg?aatcctaaac?cagagctggg?caaagcaaag?aagaaatctg?3000

acctcacact?gaaattttaa?gtttgtactt?tgaagtattc?acatcaaatt?tttctttctt?3060

tttttttttt?ttgagacagg?gtctcactct?gccgcccaaa?gtggaatgca?atggcatgcc?3120

ctcagctcac?tgcagccttg?acctcccagg?ctccagcaat?cctcccactt?cagcctccca?3180

agtagatcaa?atttctaaaa?gacaaaatct?agcagcactc?tcatttatta?aactatgtca?3240

catgcaaatt?ccttaagcat?gctgaaatac?attttattta?tttgggcctg?gagatgtgat?3300

tttgttggag?gtagcaagct?ctcttgctta?tcagaggttc?tgctgagtcc?tacaatagtt?3360

taagacgtaa?aatcaactac?tgaactgaac?agctttttat?agccttttta?agctacaaat?3420

cttcaaacct?ggaggaatat?gctctgcttc?accaatattg?taatagtaac?agctagcaat?3480

taaggagagg?ttaaataaaa?ttcatcttac?gaatctttaa?atttacaatt?acaaaaacgt?3540

ttctaaaact?ttttgttaga?gctgaagttg?agcagctcag?atactgctgg?aaaaaagcat?3600

tttccctaaa?ttcctggtta?acggttatct?gggcaatcag?atgaataaaa?cggaaaatca?3660

tttgaaacac?ctttgtaatc?accttatctg?agttcctcac?cttgcaaagg?gatattaaag?3720

tccagagaac?taaagggatt?tgttcagagt?cagacccttg?aaatggtagc?caggctggtc?3780

tagaatacag?ggctcctcat?tcatgtccgg?taactgtcta?gtgttctggg?ttgccccggc?3840

tgaagggagg?cattcattta?aaaatatgtg?ccttagttcg?cccggcagat?ctaaactatg?3900

ttctgataca?ctaaaggcca?ctgcaaatgt?tccatggccc?tttcaatgtg?cttacaattg?3960

aatatgaaaa?ccaaattatt?ctgtttttaa?acattggttt?gactgctatg?aaaaagaaaa?4020

ttcttaaaga?aaagttttcc?ttaaagaaaa?gtagcaaact?tttgcttact?aagcagaagc?4080

agtttagaaa?attgcctaat?atcaaaaaga?aatactcact?tcacagctct?gccatctgtt?4140

tgggatattt?ggccttaact?tctgttcaca?aacaactttt?ctcatttctt?caactgatgg?4200

gtcagaaggt?acaagatcat?aataaggcag?ttggtaatct?tcatgaattc?ctgtatcagt?4260

ttaaaaaaaa?ttaaattttg?atgaatttat?tcagctaatg?ccaaggcatt?aaaagatcac?4320

ctgagagacc?tattacagtg?tttcattact?aaagtaggta?tgtggaacag?agattacagc?4380

tttctctatc?tcatccacat?ctgtatccac?aagccacttc?cctgagttga?tattccaccc?4440

acaccttgaa?actaagtatt?gccatgagat?caataaagcc?tatttgaaat?gacagtaaac?4500

tatgagctgt?gatgaccaga?ttgacatttt?cccctagaac?cctattgtgc?agcaaatgag?4560

attctattct?gtaagtgcac?aggctctcac?ttgcacaggg?atatatatac?cctatcagtg?4620

agacttgaat?cttatgaggc?aagtttaagg?tgccaagtcc?ctttctctac?ttgcatctgt?4680

caataatata?tcctatttac?tacaatacag?agaaatactc?tgtccctcac?tgcttcaaaa?4740

acctaaggca?ctaggtctca?gccaagtcta?ggtccccaag?cctaagagac?tgtttcctga?4800

gtaaacatta?aaagtactcc?atctaaaaag?ctagaagtta?aaacaaacta?actctagaat?4860

acaacacaat?ggtaacataa?ttgtattctg?tgtatgtaac?tgtaactatc?aagttggaga?4920

aaataaccac?aatctcaaag?aaaaaaaata?agtttgacac?ccaggtacat?gctagaaaca?4980

gcttcctagg?tgagcctctc?aagcagctgt?ccattctaaa?gaactatatt?ccaatataac?5040

aaggggttgg?gttctgatga?gtctccagat?tcaaatggaa?acaggaagag?aatacactag?5100

gctagagctg?tgcatgtgca?caccatggca?ctgtcccctc?ccaaaggttt?catcgccttt?5160

gttttctctg?gcactcggtg?acatcctgtt?tcagataatg?gactgtacat?aatttcattc?5220

aattaaaaaa?agaagacaat?tcttgaacaa?cttctgctca?tgacaaacta?ctgggggaga?5280

ggagagcaat?ttaccaccaa?tggaacatcg?tcgagcaatt?tcccagaata?ctaagcccat?5340

tgcatagatg?tcagcacgtt?tgaaggattc?aaaatgtttc?atatttatgg?aatcatcgag?5400

aacttcaggg?gccatgtacc?taaaaaaaat?ttgcaaaaag?aactttgaaa?atcatcccct?5460

tactgccata?tttggatgaa?cctcctttca?gacatttctt?tatacataga?catatgtaca?5520

caatattaca?taacaaatat?tagactcaag?aaaaatatta?aatatccaca?ctggtttgca?5580

cattaatgat?gtcaactaaa?tcccacaaaa?tgctaaaata?gcagtttcac?actatctgcc?5640

tcatgatctt?ggtttccaat?gaaagacata?cataacaatt?gtgactgtta?aaggtgtcct?5700

aatgtacacc?acctatacac?gtactaggta?gaaaccatgc?attttaattt?agaagtcttc?5760

tcactgagga?tgaaaggaag?ggcacgaata?tactccaggg?aaaaaaataa?tagatacaaa?5820

agaatgccag?tcctcatact?gaagcttcaa?aaacctacca?aaattatggg?tcaggaccca?5880

cagagaccta?cagcaaccac?tgacaaggac?cccttagctg?gttgagaatt?gagagtcatc?5940

tacggccata?ccaccctaaa?cacgcccgat?ctcgtctgat?cttggaagct?aagcagggtc?6000

gggcctgctt?agtacttgga?tgggaaaatt?gagagtcccc?agggaatcca?gaaatctcaa?6060

aattatacat?gcaatttgaa?tagactaatg?ctgctggctc?tccagctgtc?tccaaggcca?6120

agacagtagt?ttgaaaaaat?gctgtgacag?cttgtgataa?ggggtttggg?tcagaaatgc?6180

ccaggttcaa?atctcagctc?ttcggcttat?catccacatg?aagctggcca?tattatttaa?6240

cctcctcaag?gtggtttcct?catctgtgaa?ttaaagggta?ataacaccta?cctaattaag?6300

ttcttttgaa?gactcatgga?ctcaacaaat?atctactgag?gatctaccat?gtattaggca?6360

ctgtgatgga?tgctgggaat?acaaggctgc?tctcaagcag?cttgcaccta?atagaatata?6420

taggcaaata?aataaacagt?tacaacataa?cgcataagtg?cctcaacggt?cccagttcag?6480

tgtgctatga?cagtccctgg?cagggactcc?taagattttt?gaggactaga?aaaaacttcc?6540

tacgggaaag?gtgggtatga?ggctgagaaa?cagtagggta?aagtatgctc?caggagacag?6600

catgtgcaaa?agttctaaga?aagcaagaaa?ggcatatttt?taggaactga?aatatgaaaa?6660

tagcagggct?agctactgca?cagtatttga?gaagggatta?aatgaggtaa?tatacgtaaa?6720

agacctatta?gacgattggc?acatagtagg?tgccctataa?acgttagtta?ctactgttat?6780

tataattaac?atgcctaatg?atattttctg?gaagggcaac?ctttcatcag?caggcatctt?6840

tttaagtcag?gtaactctgg?cttcagagca?ggcaagacca?tgagatcttc?ttacctgttg?6900

gcaatctaat?aaagtgcaag?tttaagctga?gtttcagcaa?tgatatgtat?atatgaaaga?6960

gaagggaaaa?aaggtgattt?cagaagatat?taaatatagt?tgttcaaaag?tatacctttt?7020

tgttcccact?ctgtggtttg?gagcaatatc?aatggtatct?gtggctgaat?catgtcttac?7080

tgccagtcct?aagtctgcaa?tacagcaagt?tccattcttc?tttaccaaga?tattctttga?7140

tttcaaatct?ctatgagcaa?tggctggctt?tcctaaagaa?tcaaaaatta?aacatgactg?7200

cttaaaaggt?aataccaatc?acaactcaca?tctttaggtt?caaaagtctc?ttctcccaac?7260

ccaaattatc?aaagcatttc?agcccacatg?acctacaata?cttacgggca?ttattaaact?7320

caagtgaatc?actacaccaa?aagtcactga?atttatattt?ctttaaagaa?aatgtggaca?7380

ataacatgct?ttaaaagatg?aacaactcaa?agactggggc?aaaaaaaaag?ttatcagttt?7440

atctgttggt?gccttatgaa?ttctttttaa?gaaacttagc?catagactga?tattccagca?7500

gcccaggaac?caagcatgta?gaacatcact?tccctatcaa?ctgcaatgta?ctcagtatta?7560

agtatattat?ctttgatgct?aaccactaga?aaatgttatt?aaaaaataat?aattataatg?7620

tggaaaacct?ggaaccttca?tacactgctg?gcaggaatgt?aaaatggttc?aggcacttta?7680

agaaaatagt?atggcagttc?ttcaaaccat?taaatagagt?tatcatatga?tacagtaatt?7740

caactcctag?gtatataccc?aagataactg?aaaacatgaa?actacataca?acttgtacac?7800

aaatgttcac?tgcagcatta?gctacaatgg?ccaaaagaaa?caaaccaaat?gtccatcaac?7860

gaacggatat?atgacatatg?ccatatccat?acactgaagt?attacttagc?catcaaaatg?7920

actgaagtac?tcatacgtgc?tacaacataa?atgaaccttg?aaaacatgct?aagtgaaaga?7980

agccagtcac?aaaagaccac?atattgtatg?attcatttat?ataaaatgtg?cagaataagc?8040

aaatctacag?acaaaaagga?gcagttgttg?cctagggcta?aggagtttgg?gaggaaaggg?8100

gagtgactgc?tagtggctac?agggtttctc?tttggagtga?agatattcta?aaattgactg?8160

tagtgtttgc?tggctgtaca?actcttgagt?attctaaaaa?ccactgaatt?ttacacttta?8220

agtgggtgaa?ctttatgatg?tgaattataa?ctcaataaaa?ctgttacaat?caataataat?8280

aataactaca?aagatggagc?taagatgtga?actagcactt?atgctgtatg?taaagtgggg?8340

agtgggggag?ccattgggtt?gcaagtggac?aactgctaga?gcagagagat?atactggcat?8400

ctgaaatccc?acatgcacaa?aaactacagc?atacaaatgt?cataactaaa?acttagtatt?8460

taatttttca?actgtaaaac?tatctcatgc?agtctcctta?tctcaaggtc?aaatataatt?8520

attagatggc?cagataacag?ttacctagca?tgttgatgtt?tacaaagcac?tttcacattt?8580

catttgatac?tacacataaa?aatatattca?gttggacctg?aattctgaaa?ctgagatcct?8640

caaaaatcat?aagattgaat?gctactttta?agaactcaaa?aaaaatcaca?gttttgttac?8700

aacgactaga?gaatctctaa?acaaatttcc?agattcctag?ctctacctga?aattttgaac?8760

tgaaagataa?aatgttctca?tctaaaaaat?ttgttttaaa?tatctccagt?taggccacct?8820

actgtttttg?tttttgtttt?tttttctgag?acagggtctc?tctctattac?tcagctggga?8880

gtgcagtggc?atgatgtctg?ctcactgcag?cttcgacctc?ccaggctcag?gtaatcctcc?8940

tacctcagcc?ccctgagtag?ctgggactac?aggtgcatgc?caccatgccc?gactaatttt?9000

ttgtatgttg?gtagagatgc?ggttttgtca?tgttgcccag?gctggccatg?aactcctgag?9060

atcgggcgat?ctgcccacct?cagcctccca?aagtgctggg?attataggca?tgagccacca?9120

ggcccagcct?ccaccttcta?ttttcataga?cattattcat?gaaaatttaa?agcttaaata?9180

atagaactgc?ttatagaatt?accttgggta?ccaacaatct?ccatgtgaag?atgggcaaga?9240

ccgctcgccg?tggacagagc?aagttttatc?attccttcca?cagtaactgt?gtatctgttt?9300

aagtaatcaa?aaagggatcc?atgctcatga?taatctgaca?ccaaccagag?ctgagtccaa?9360

gtaccattgt?ctgtaaaaca?gaattaacat?ttcggttggg?ctgcagacca?tttatgattt?9420

atttgttcaa?tggttattac?tttttactct?caatcctgag?tcacacactg?caatataatg?9480

ccaccttaag?tctgtatttc?cttcacattt?tcttctacat?tgtttgtttt?atacttttat?9540

gtacacatcc?tttagttcct?cagagtaagc?ccctcttctt?gagataaggc?aagtataatt?9600

aatcccattt?aagagacaaa?gatggtgact?tttttgagtc?ttcacagata?attggtatca?9660

gagctggcac?tcttaagtgc?ctagaaaaat?ctctgggtcg?ggttgggtgc?tcagtggctg?9720

ttcctggaag?gagagaaggt?taaaaaaaag?gaaggaacag?agagggaagc?aaggaggtga?9780

gaagtctccg?gagaccagtg?tggccacagt?gggaatggaa?gagtatggga?caaaactgaa?9840

agtgagtttc?aacaagaaat?gacaagcttt?agtgacagat?tgtgtacaca?gttcacaaag?9900

acgcaagaca?agatgattat?gattccaagg?ttgctagctt?agaaaaacag?aaatagtgat?9960

acctctaaca?catggggaag?ctgaaatagg?aactgaaatg?tcaggagcaa?aactggaaaa?10020

gctgggacta?aactcaaaca?acgaggaacg?tgggttccaa?aatttcctct?gtaagccaaa?10080

acacgagttt?aaaacatgtt?ttctcatagg?aataatggta?aagacactag?ctaggctcct?10140

aagctagact?ggtccacgac?aatctaattt?aacctagaag?tagctggaaa?accacatgct?10200

taattaagcc?atgaagaaaa?aaagcattac?aacattagga?gacagcacaa?tccagtaaaa?10260

gatggacgct?tagagtcatt?ctaacctggt?tggaatccac?ggcctgcctg?ttactgacaa?10320

ggagcctgtt?tctcctttta?tacaagaata?aagtcttact?ttgtaagact?gttaagattt?10380

aaaaaacgga?atgctagatt?ctttaggtaa?gaagtacata?aactgtgctc?tttctttccc?10440

tgctggttgt?aaaccaaaag?aaaaaatcca?tattgacatg?aaacagcttc?tattttgaag?10500

gtatttggtt?gaagaagaaa?accaactctg?attagaagag?attaagaaag?gaatagaaac?10560

ttttcagaag?attctggagg?agatttctgg?gtacatttaa?aaggacttag?tattaatttg?10620

ttcttcatga?actttataaa?ctgattctga?ccaaactcgc?acccttgctt?ttccttgata?10680

taggcacatc?actagcttat?ttgcatgcct?cttaaccatt?actgaatttt?gaaaagctca?10740

caaatacaag?aaacaaagtg?gaagacaggc?agatggaaga?aagggaaacc?acaggttatg?10800

gacaagatag?aaggaaggtt?atatgtaagg?ggccataaat?ataaagggct?gccgggggtg?10860

gaattaacta?aatcaggaga?agataaagga?actgaggtgg?aggggctagg?ctcagagaaa?10920

gtacattaac?ccctgacaaa?gaagaaagaa?ggggagtagg?gaagagccag?tagggtcagc?10980

tagttcccat?ggtgaccacc?agatgacagc?atcagcctgg?ttagaagttc?agggcacaga?11040

ctcaccaaca?ttttgtgctg?ctgtgtttgt?aacttggaat?gtgacaaaat?ccagaccctg?11100

ggtgaggttt?aagctttcaa?atggagattt?gagagttgcc?aacatggtag?agtttgaaac?11160

catgaatgtg?gctatgttct?taaggaagaa?attaccactt?ataaaatcag?taccttcata?11220

tgaaccagtg?agaagagtaa?gagttgagaa?aacaaagaca?actatgaaga?agtaagaagg?11280

aacaaggaaa?gtctagggtc?atcaaacaca?gtaaataaag?aaaaggttgt?tttaagagtt?11340

gggggaggaa?ataaatggtg?ataaaggcag?aaacgaaaat?gagaactaag?gatttggtca?11400

gactgattac?tattttttgt?tttgttttgt?tttgttgttg?tttttttttt?gagacagagt?11460

ctccctgtgt?cgcccaggct?ggagtgcagt?ggtgcgatct?cagctctgac?tgcaacctcc?11520

acctcccagg?ttcaagcaat?tctctgcctt?agcttcccaa?gtagctggga?ttataggcac?11580

ctgccatcat?gcctggctaa?tttttttgta?tttttagtag?agatggggtt?tcatcatctt?11640

ggccagccag?gctggtcttg?aactcttgac?ctcgtgatcc?acccaccttg?gcttcccaaa?11700

gtgctgggat?tacaggcgtg?agccactgtg?cccggcctgt?tttgttttta?acttaagagg?11760

tattacattg?tcaggtgcca?ctgataatcg?ctacctacat?tcatcatata?cctcactgcc?11820

ccgtcttaat?caaacactat?acacctccac?atatgatgca?ataggatgta?tataatatcc?11880

ttagtatgta?ttttgagaaa?accaataaaa?ctccaattag?gtttagcttc?taaatctaac?11940

taccagtttt?cagaaaagat?agaagaacaa?gttaagagac?actatggaaa?tgcaatcagc?12000

aaaatccaga?atgtgatagg?cccttcagga?taaacaatcc?aatttcttca?acaaataagc?12060

tgcgagagga?gaaaaaagat?gaagggggga?cctaaatttt?aagacacata?agagaaatat?12120

caactaaata?taacttgtgg?acttagaatc?ataatttgaa?taaataattt?ttttaatagg?12180

agacaattat?agaattgaac?ctaactggat?atttgataac?atttaaaaaa?ctgacaatgg?12240

tagtgtggtt?gtttcataaa?aacatttcct?catcatttga?agatacaaat?tacattttat?12300

aagtgtttac?agatgaaaac?atattgtctg?ggaccagctt?caaataacac?agttagggca?12360

gagtaggtgg?gatcagacat?caattatgat?tggcagtgac?ctgacaactg?ttgaagctgg?12420

acgatgaggg?atcactgtaa?ctactctgct?tttctacata?ttggaaattt?tctacaaata?12480

aaagtcaata?acaaaaaaaa?gcagtacatg?cttgtaaata?aatttgaaaa?cccagagaag?12540

ctaaaagaaa?aataataaaa?atcacccata?attaccaact?gaggttaaac?actgttaata?12600

tttgaataaa?taaatattgc?tgaagtaaat?ggaaggtggg?agaaggaaaa?agatgactac?12660

aggtctggcc?aagctaagag?ataatgacag?catttttttt?tttttttaaa?taggaaagct?12720

gggaaataca?tttgattcag?gggtagggat?gacaagagtg?gagctgaaac?acaagtctct?12780

gacagaggca?gtaaaaatag?gaatcgtggg?ggctgggcac?agtggctcat?gcctgtaatc?12840

ccagcacttt?gggagggtga?ggtgggtgga?tcacgaggtc?aagagatgga?ggccaacctg?12900

gccaacatgg?tgaaacccca?tctctactaa?aaatacaaac?attagctggg?catggtggtg?12960

cacgcctgta?gtcccagcta?ctcgagaagc?tgaggcagga?gaaccacttg?aacccaggag?13020

gcagaagctg?cagtgagccg?agattgcacc?actgtactcc?agcctggcta?cagagcgaga?13080

ttccatctca?aaaaaaaaaa?aagtaggaat?catgggcata?aaggtattaa?cggaagctaa?13140

gaaagtggca?gcagcacagt?ctaaggtcac?tgcttgcagt?ccccactcat?tctgactccc?13200

tgctgacagg?cttccttcct?tcttcagcat?ctgacctgac?actgggcctc?aggcaccagc?13260

atgataggca?gaaaagtgtc?cgtacagtta?ccagggtggt?tgaagaaaca?atttatctct?13320

ttgagtttgc?cagaagattc?atctatttag?cccttggcaa?ctcagaacac?tgacaagtta?13380

tttttactct?ccccattaat?aaggtcaata?gtccatattg?aaacatccta?ctggtcagga?13440

agagattaaa?aggaaacagc?tatctgagcc?ctattctcaa?aattttgagc?aagtttatat?13500

atcttttcta?tatcatgagt?actctcaata?actaactgcc?ctaaactaaa?ccaacaaagt?13560

acatggcttt?ttaaaatagc?tcttttatat?tttataaaac?attaagagat?tttaggaatg?13620

ctatcaagag?tcaagaaaat?cttgaagaag?ttcctagttc?taaaagttac?taatatattg?13680

tattcgactt?aatgggtcta?atctacatga?gagacatcta?tgtctcatct?actttgatga?13740

tggttagtca?ccatatctgt?aaagacttaa?agagatcttg?ttatatataa?cataaggaaa?13800

agcaaatgtt?acagaccttt?attgtctgct?gctataaatc?ccaggatgtt?ttcatgacgt?13860

aacattacag?tttgataaat?ctctgcctca?cggaaccacg?aacgttcttc?tctagaggag?13920

aatatcttaa?cagcaacttc?ttctccccgc?cactttcctc?tccaaacttc?tccaaatcga?13980

cctttgccaa?tgctttcttg?taacacaata?gttctcgcaa?ttgttctctg?aacaagcaat?14040

ggtaaaccta?aaggtaaaaa?taaatagtac?tcaacacaat?caacaatatt?acatgtttca?14100

aacatcatga?taggcactaa?tgagtgaccc?agaaaactga?tactttaagc?tatcccttta?14160

ggaatttatc?tcactgggga?gatattatat?ttgcaataaa?ataactaatt?aaaaaaggaa?14220

aataagataa?taaatataat?aaaagaatcc?agaaactcct?gctagagggt?caaggtaggc?14280

tttgtaaaag?taagttgaat?tttgactatc?ccttaagtac?ggtggttagg?caggaagaat?14340

gtgcaggcaa?aggtagaggg?aaatgaatga?cacattttta?gggaagcagc?ttgggcaatc?14400

agagagagga?tatatgtggc?aaagcagtga?aaagagaaag?taagctgtca?ccagaagatg?14460

aagagtactg?aataccaagc?tcaaaataac?caatgaagag?ctttaggtaa?aagaggaacc?14520

tttaaagatt?tctgagaaaa?agggccatgg?ctggaagcaa?gataatttta?aaatcttatt?14580

ttagaaagat?gaatctcgta?acagtttcac?tgatgggagg?aaaaaaggat?gtgaacgcag?14640

aaacacagaa?gtaaattctg?gctttttgat?aagtcagtaa?aaatcaccac?agaaactatt?14700

tcaaggaaag?caatttactt?gctgacaact?ggctacatag?acaacactag?tatcttgaag?14760

aacaaggcta?agtaacttac?cttggtaatg?gagcactgtt?tttccactaa?tggaacttgg?14820

ctttctccaa?aatatgtatt?tttaagtatt?gccatactta?cttcatttaa?aagggtttac?14880

taacttacct?gcaacattta?agtggcacta?tatgtgagac?catcacttaa?tatcctatcc?14940

accatccggt?aagtgtcatt?ttaaattaca?ttgacactaa?caaagaaaat?gccagtgtac?15000

atcatgttcc?tcactcatat?cttatttata?caatctatgt?acatataaat?tggtgtcatt?15060

tataatctat?actcaaagct?gcttactaga?tcaaattaac?ccaatgacag?taaatgaaat?15120

tatctgctct?ctttggttcc?ctgatgtgaa?atgcttataa?atccaaacgt?taaatcttta?15180

aagcgatcag?aagctcttct?tcttaagttt?ctcaaacggg?tcctttcttc?ctcttgctct?15240

accctcccca?cctcctgtaa?agtagttagc?agtataacta?taaataactg?tttgtgttta?15300

taaggaggct?gctagttaga?aacagatctg?tcagaaatcc?ttatttaaat?catagagctc?15360

tttcgcacta?tgtataatca?attctaatta?tgttgtttag?tgtagatact?aatttattac?15420

attttatgaa?agccttgtag?agggccacac?cacagactta?aaagtacact?taagagttaa?15480

tttcaggaga?ctaatctgga?aattgcaaag?acaagtaata?aaaaagaaaa?aggaatcaca?15540

aacacaaatt?ctgaaaacac?ctgacaggtt?caggacttgt?gtaaatggta?tggtcaagaa?15600

aggccaacag?gacgaggaaa?ggttttgtct?tcccctttat?cactggattc?tagatgtcaa?15660

ttaaaattaa?aaagcaaatc?ttgatccact?gtattatcta?tattggatta?cttcacatga?15720

atagttgagc?atttttaaaa?agttaacaat?tggccaggca?cagtgactca?cacctctaat?15780

cccagcactt?taggaggccg?acgtggttgg?atcactagag?atcaggagtt?caagatcagc?15840

ctggccaaca?tggtgaaacc?tggtctctaa?taaatataca?aaaattagct?gggcatggtg?15900

gtgcacacct?gtaatcccag?ctactcagga?ggctgaggca?ggagaattgc?ttgaacccgg?15960

gaggtgaagg?ctgcagagag?ctgagatccc?accactgcac?tccagcctgg?gcaacagagt?16020

gaaactccgt?ctccaaaaaa?aaaaaaaaaa?aaagtaacaa?ttttcttcta?aagacaaaac?16080

tgaataggcc?taatttagat?ctctatattc?tctgctctac?tcttctgtac?ctttagaact?16140

gtttgagaga?aaacttcaaa?agggaaacag?ggactccaca?gctttacatg?cagtgaacag?16200

gaaataagac?ccgaacaaca?tgcatatatt?acaagagctc?ataagctgca?cacgccataa?16260

caaacactgg?cctagaagac?tcacttacaa?aagctggcac?atatgcacat?gtgcacactc?16320

acacacttgg?cgtacagctg?ccagaaccca?gctcttcatt?gtattccctg?aagttcccaa?16380

gttaaaagca?cagtctttag?aggtagagac?agggcctttc?cttaattatg?gtcacggtac?16440

taagtaataa?acatatgaat?tcagaatgtg?aaatgcttat?accttttcct?caattaatga?16500

aagaactaaa?aacagagtat?tacaaacaca?cagtttactt?attcacaggc?actagtctca?16560

tgcctaaggt?ggcattaagg?atttataatg?aatagaaggg?aaacagatgg?cattttctgc?16620

tattattcac?cagaagatgg?cttctgcctg?gataggtttg?gagggaattc?agtacacaat?16680

gaactatgac?aggcaaagga?ggccttaaac?taagttttgt?acaatgtggt?caactgatac?16740

tgtatgttag?atttttcctc?caagtatgtt?ttcaataaga?gtaacacttg?tcatttggac?16800

ataactctac?aatttaccaa?gtgctttcat?gcaaacattt?tgtcttgctt?gaactcacaa?16860

caatccaatg?atgtgcacag?aatccatcac?tttcatttta?aagatgaaat?aactcaagca?16920

tgagacattg?gttaactgcc?caaagccaca?gagctagcaa?gcaatgcaga?caagtttttg?16980

cagggtaagg?catcaaagga?gggagagaag?ctttcagaga?acagagagct?atggtccctc?17040

atggatctag?aaatatatat?atatatatat?atatatatat?atatatatat?atatatatat?17100

ataatggaaa?cagaattatt?ccattgtttc?tcatgtttat?atcttaaaag?gttaatgaag?17160

atattcttat?ccagtaatca?actgccaccc?acccaccaat?tcctttaatc?agttaggtgg?17220

gcttattcca?ctgtggcaag?tggcatgagt?gctgtgtctt?tccggagtat?aagtttagaa?17280

acaagagaac?aggtttgagg?gattaattcc?aaatatctgt?agccatcctg?attttctgtg?17340

actctggtcc?ttgattatca?cagttttgag?caggatgact?tccagaatga?gcaaaatctt?17400

tttgaagatc?tgaactgaga?ataaatggga?agtcccagga?aagctctaaa?ataacctctg?17460

tccaccaggc?ctgcctaaag?actatcacac?cttcagtact?aagactgctt?catctaagtc?17520

caaactctca?ttgtcttcct?tgcacaactg?tttcaggaat?ccctaagctt?gccttctggg?17580

acgtgagctc?cagtgcgagc?ctgtgtgtgt?cctagtagtc?aaggagagag?ctctcttatt?17640

gaatacatat?ggccaaattc?tatagaagaa?taattcaggt?aataaaatca?gtttcttcat?17700

tcttaaatga?atggatatgc?atacatacca?atatatattc?atttccttaa?aataaataga?17760

catttgtcat?tatatgagct?ttctgcaaca?ttagatgtga?ttttatgctt?cagaattata?17820

ttcttaccca?gtcacaactt?ctgctttaac?attcctttaa?tatcactcaa?ttataaaatt?17880

agtgaaaatt?tttttttttt?ttttttttta?gatggagtct?gtttcccagg?ctggagtgca?17940

gtggtgcgat?ctcagctaac?tgcaacctcc?accccccagg?ttcaggtgat?tctcctgtct?18000

cggcctcccg?agtagctggg?actacaggcg?catgccacta?cgcccggcta?atttttttgc?18060

atttttaata?gagatgggct?ttcaccaaaa?ttagtgaaat?tttcattata?tacgctttac?18120

aaattttcac?tttattcatg?aatttagccc?ttatttgaag?atgactcata?cttttcaaag?18180

gatagtacat?ctcatttaaa?agtcttaaca?aaccacttga?agtgttttta?tcaacagtat?18240

gggttccata?tttttgatga?ggaaacagaa?gcccaaagag?gaaacatgtt?ctaaccaagg?18300

ttatacagcc?aatcaatgac?aaagcttgcc?ttgaaaccta?gatctattta?ttcttcacca?18360

agtgtcaaat?tctaaaaaca?caggggatag?gagtgttcct?ctcttaatat?ttttccaaac?18420

cacatacatg?caagaaaaag?taaaagataa?ccccctttca?gtttaaacat?gaagcactgc?18480

tatgccaaaa?tccaccttgg?gatgactctg?acaattagct?catctacttc?tgatgccaca?18540

aatatcaaca?aatagaactg?agaaaagaaa?acgtcattag?gggccaaaac?tacattaaat?18600

aagaaggtgg?ttagacattt?ttctcaagtg?agaaaatgac?ataagagttc?attagtttaa?18660

ttttaaaaaa?ccaggcctat?acgaaagaca?atttcatata?atgtttaaaa?agtaaataac?18720

cttcacaatt?ctgaatacat?ttctgtcatg?cctgttttca?aatgtaaaca?tcaagctgct?18780

aaacaatcct?gaatagaatg?ggttagctgc?agatcatgtg?aatatctttg?accttcagct 18840

tcatctatat?gagaataatt?gttcttatcc?tttctacctc?acagtgatga?aaagcaaatt 18900

agattataca?agtgagaacg?ctttgaaatt?tataccacca?tggagctgac?ttattgattc 18960

gctttaacag?ttaaagttaa?gttccaatct?attttaaacc?agccacagtc?atatatacat 19020

caagcttaaa?gatttttatt?aggttcaaac?ctgcaatatt?atttatacta?tctcacattc 19080

tagcaagttg?gcttattaga?aaactaataa?aataagtatc?gcttaatttt?aaaaagatgt 19140

cttaggaaaa?aggagaaaca?attatgttac?ctgagccaga?acctgacgtt?gtcatatcat 19200

aaattaagtc?tttcaacgta?gtaccctctg?aaataaaagg?gcgatctaat?gaagggtcct 19260

cttcatttgg?cactcgatgg?tgaatgacag?tgcggttgtg?gcagatatag?accatcaaca 19320

tgagtgagat?gcagacgaag?cacactggtc?cagcaatgac?agctgccagt?tccacaggac 19380

caaggccagg?tgatgacttt?actgaaaaag?ggcctcgagt?gaaataaaca?tcaacaacga 19440

caaaaacact?gtaggtggca?acccccattt?tcccaatcct?acacaattcc?tgcagctggc 19500

cactgccacc?acttagccaa?agagcctcat?tacagcagtt?tacagggctc?aaacccagaa 19560

caagtgaatc?agtcttctcc?cactaggcct?ccttttatgc?acaccagctc?tgtcagcacc 19620

cacttactcc?tgtattcttc?agccatcatt?acaaggccaa?ctgccgccaa?tatcatagga 19680

ccttccccac?ttatcacatc?aggtcactaa?taccaataac?ctgtaacaat?acctattaac 19740

atctccttaa?aaatcatatt?ttttttaatg?tttggcttgt?cttcttgttc?caaggccagt 19800

acatgctcat?agcaagaaaa?acaacaacaa?aaaaaacaac?aaaatatcaa?aacaagcgaa 19860

aaaaaaaacc?acatacatct?tcatcacttc?taaacaactc?acatttcagt?atatatctct 19920

ccaccaattt?tttttttttt?tgagatggat?tttcactctt?gttgcccagg?ctggagtaca 19980

gtggtatgat?gttggctcac?tgcaacctcc?gcctcccggg?ttcaagcgat?tctcctgcct 20040

gagcctccca?agtagctggg?attacaggca?tgtgccacca?cacctggcta?atttttgtat 20100

cttaatagag?acggggtttc?accatgttgc?tcaggctggt?ctcgaacccc?taacctcaag 20160

tgatccacct?accttggctt?cccaaagtgc?tgggattaca?ggcatgagcc?atgcccggcc 20220

aataggtcca?ccaatttttt?aaaggcagaa?catatctttt?actttttttt?tttaacagag 20280

tttgcatata?tatacttttt?atactatctt?aacctcctgg?acttttaagt?ccagatcatt 20340

ttcttgtaac?ttctattaat?aattaagatt?ttctggttgt?ttcagaaaat?tacaattatt 20400

ttgacattca?tcctgagtct?tactggttta?ctgcttacca?ccatttcttt?catatcacat 20460

ctttcccatt?cttaagatct?tcagtagatt?aatctcttat?catacagaat?cctatttcta 20520

gtaatttctt?tcaggaagag?tccatgcacc?cttgtacact?gaacttagtt?gtggcaagaa 20580

ggctgttgcc?tttgtatatg?aaaaatcttg?gcctatttca?agaattttag?gtgatcgtaa 20640

aaatgttcca?tttgcccttt?gatatttaag?cagaaaatct?gaacctgttt?ttttttttca 20700

ccttttacag?gtaaccaatg?tttatgtgtg?ttaaatgctt?atataattct?tttattcttg 20760

aaattgatac?tttttattat?atgtgtttgg?attaatattt?tttcattaat?tttgcctggt 20820

attctgtctt?ctttatgatt?tcatgccttt?ttctggaatt?ctgataataa?gcatattgga 20880

tcatctaaat?ctgttcccta?tatctcttaa?tatgctcacc?aactgtcttt?tctctgaatt 20940

gtaacacagt?ttcttaaaac?ttgtcccaaa?cttgactata?aaattatggc?atccagtctg 21000

ttgttcgctc?tcaatagtgc?atttttaaaa?acattcatca?gttgggcttt?tcttctgaaa 21060

gcaaccttta?acaactgtga?aatgttctca?tttcatagtg?aataactgaa?aatagaccct 21120

gtactgtttg?aaagttcttc?cctatcatgt?ggtaaaccta?tttcacagga?tgacatctaa 21180

tctatctagt?tcagactact?tcttttgaac?tcctaacttt?tcattggtaa?ttttttgctg 21240

tttgcttatc?ctagagctgg?aaatgagaag?tttatatatg?ttcattagaa?acatgagaaa 21300

taaggtgact?tcttcacaag?gttttgtaaa?tatctattca?gatatttcaa?gctcaaatga 21360

tggaaatggg?aaattctgga?attatccttt?tctttgccac?attataactg?cagatgcttt 21420

catcaaagtc?acaaagatat?tgtagtccga?ccaaccctta?ccacagggga?gctgcattat?21480

catgctgaac?aggtggagga?ctggcctttt?ccttctgcgc?tacagcagtg?cttcctcctt?21540

taattagcac?aaggcctgga?ccaactttga?gtggagagtg?agcaactgtg?tctgctcctc?21600

tgagcactga?agccaggtgc?ttcctaaaag?ggaactgaga?gtttgccccc?ataccctaac?21660

ctcacccccc?aaatcctttg?tctaagttat?tggctggact?tttcgatgac?taacctttct?21720

tatatggcta?gtcaattctt?tactagtctg?gtgtcatctg?tactgtaaat?tgcagaagtt?21780

cctcacaagt?gctggcatgt?gggtggcatt?ctaccattaa?tcccactagc?attaatacag?21840

gttgccctca?tttttatatt?cctttgggat?ctggggaaag?aggtaagagt?taaatacatg?21900

tgctcagact?tccatattaa?accggaatct?taaaattaaa?aagtttatga?agtcttcaaa?21960

ctgctggttc?tgccaggaaa?ttttatttat?ttatttatta?tctttttttt?ttagacagag?22020

cctcactctg?tcacccaggc?tggagtgcag?tggcacaatc?ttggctcact?gcaacctctg?22080

cctcccaggt?tcaaagattg?ttgtgcctca?gccacccaag?taggtgggat?tacaagcatg?22140

tgccaccatg?cccagctaat?ttttgttatt?ttagtagaga?tagggttttg?ccatgttggc?22200

caggctggtc?ttgaacttct?ggcctcaagt?gatctgccca?cctcaggcct?tccaaagtgc?22260

tgggattaca?ggcatgagcc?accgcaccca?gccccaggaa?attttaaatg?taaactacag?22320

gtgaaggacc?aaaaatctag?aaatcatgta?taattaattt?acgcaaaaag?atcataaaac?22380

aagctgaaat?tacaaaatga?aaacatctag?actgttaagt?gctgctctga?atccccactc?22440

attaaaagac?tgtgattgct?ttaaaagata?ggagcattat?acaaggaaga?agaaattcac?22500

tctgagaaca?aagtagagac?aatctgaaga?tgttgttgtg?ggctttgtca?gagtttgctt?22560

ttatctatcc?ttttaggtat?aacagacctc?agaggaagtc?caccctggaa?ccaccttctt?22620

aaacaacaca?tacccaggag?gcaggatctt?ggttactctt?ataagtctgt?aacaatggac?22680

aagtcacttc?ttgcctctaa?acggaatgag?ctggattaga?caatttttat?gatcccttcc?22740

agttctaaaa?tcacagagta?tgaagagttt?ttcttgtagt?atctaggaaa?aaaattttat?22800

acaacttacc?agtagttgga?agttctattt?tattgcaatg?gtcctgattg?cagcaatatg?22860

ttgtagtcac?agacccagtt?tttgaagagg?gtgcacatac?aaacggccta?tctcgaggaa?22920

ttaagtcaat?ttcagctata?cacatgctgt?tgtgtataac?tttgtctgtg?gtctctgtga?22980

cagagacaaa?gcagagccca?tctgtcacac?aagtaaaatt?gtcttttgta?cagaggtggc?23040

agaaacactg?taacgctgga?aaaagagaaa?gattcttaga?aaaaatctca?aggttaacag?23100

tttgaaatta?tccaatattc?acctctaata?atacattctt?gatcctatta?tcacacaatt?23160

tctatgcact?gtttgttgct?cttagaagca?aaaaacaact?atttgttgct?cttagaagtt?23220

tcaaattata?ttaagaacca?catacacgtg?gaagcccaag?gaaatgtagc?aacatttgga?23280

cccaggtttt?ttcctgaagt?tttttgcttc?caagtataga?aaaattttgt?tatgttcaat?23340

ttcatcaaag?caaggcaagc?atttgccttc?ccattagaaa?caaagtacat?ttaaatttgt?23400

aatggttata?cttttttttt?tttttttttt?tttttaccag?gcccaaacta?aacattcaca?23460

tactcctcct?ttgagaagca?atgtgtgaaa?acactaccac?ccattaagtg?taggctaatg?23520

ccatttcagt?ggctttctgg?ataatggagt?aacggaaaca?gatttgtact?gagccagaca?23580

ctctctattc?cccttggtgc?aaaccctaaa?aaagacatgt?atattctggc?caggactggg?23640

gcattctctt?agggaagcca?agcagactac?acctgtaaca?atacatacat?gctccaacca?23700

cataggcaac?ctaactacag?aaatgactgg?cagcaaaata?ctagcttcat?gcccacttgt?23760

atctacttga?tctttatggc?tcaaccccag?gagtgacctc?tttagggaag?ccttctaatt?23820

atcaccaaca?ccttctcata?cacacagata?caccttcaac?catgctctct?gatgaagtta?23880

agtgctctcc?aaaacacata?ctgcttacca?gaattgctag?ttttgttttt?ctttctccta?23940

tgaaactgta?aactccttga?ggccagatac?ctgtattagt?catttctgtc?aatctgccat?24000

ctaacaccat?gcctcatgca?cagcagcatt?caaaaaatac?ttgttgaatc?acaatgatag?24060

aatgtgtgca?taatttcacc?atggtcacat?gaaattgcaa?agcacagaca?tgttcttaaa?24120

tccaaacatt?ccaattactt?gttggcaaag?gaataaaaag?gagtctaggt?acacggaatg?24180

gccatctatg?acgtgaacag?caaggtccac?tctacctaga?aaaggagtgg?ctaggcagac?24240

aggggcagga?tagacagagc?taactccctg?aagagctaac?ttgctgtaca?agaaagggtt?24300

aactcagcag?gactgagttg?ctcaaaccct?gcatattccc?aagaaagact?tgtcttcaaa?24360

actggccttg?gctggctcct?ggtagatgag?ctctgaacct?ttggaatatt?ctccctgata?24420

agaatatttc?tgtatgcctg?aggccttggg?tcacatggta?ccaattttgt?cagacagctt?24480

attctaacaa?tgtgatttac?agtgaacacc?tattactgct?ggggggccgg?gtaggagaag?24540

tctgaggggc?tgaagcctgt?catgcagatg?ctgcaagcct?aagtgactga?ccaacagtaa?24600

aaaccctgga?caccaaggct?caagcgaact?tccctggttg?acaacttcgt?gcatgctgtc?24660

acacattgtt?gttgagagaa?ttaaggccat?ctatgctatg?ccactggaat?gggacacctg?24720

gaaacctgtg?tctgatttct?cctagacttc?accccgggtg?ccttttgctt?ttgctgatgt?24780

taactgtatg?gttttgctgt?aatacactat?aaccatgact?gtaacagctt?ttctgagtcc?24840

tgtgagtcct?tctagcaaac?caagtctgag?gatggccctg?cagactccca?actcacttgc?24900

tcaactcaaa?ttcaggaatg?tcaggttctc?cctcaagtag?ctgtttcttg?gttgctggct?24960

taattcacat?acttgtctat?tatctttaca?gaccagtaaa?gttttacctt?aatcattatt?25020

aaaaacgctt?tctttattca?tagacaggtc?agctatttgc?ttcctaagta?tgaaagaaac?25080

tcaaggaaat?gacaagaaag?agacacaatc?gtaataaaga?ctgctaaaag?agacagtaat?25140

tattcatgac?aaggtgtgat?ggtgatggct?gtctgggtat?gatttcctaa?ggaggaattc?25200

tgaaccagga?attcatggac?tggcttcaga?ggtacatgaa?tcccataaaa?ctataagcca?25260

aatgttatat?gtatttacat?tttcaaggaa?aagctttcca?agtcaatcac?aatggagtct?25320

gtgacccaca?aagcattaaa?actaccaccg?aaggacattg?tcataattct?ctcctaaatc?25380

ctctttactc?atgattagtc?attcaaccca?tgttttctaa?gcattacttt?tatcagttac?25440

tctaccaaaa?gcttagcaca?caaagattaa?taactaatgg?tcacagcact?tgaagagctc?25500

caatgacaag?tgaaggagaa?cactgtaata?caatgtggta?accgctatac?ataaaaaata?25560

ttgccctgaa?tactctccca?gttctcagat?caccatggct?cccctatgct?gatgagataa?25620

gggctaaaca?cctagcctaa?caagactttt?agtttggggt?tccaatttac?ttctcacatg?25680

gcaaatgcta?tctagggcca?cacacctctc?accattataa?taataatgtc?tttcatgacc?25740

ttggtcttta?catataccat?ctctctgtct?agtttaaacc?tatcttctta?tctgactcat?25800

cctttaagac?cctatttcaa?caggatcttt?gccattatgt?gctctaaacc?tcgcccttac?25860

cttcacaata?attggtatct?cctttcaata?tgttccatag?tgctctttgc?atacctttag?25920

aacagcacaa?atcaatctat?ttatagcttg?ctgttaaagg?gtctttcatt?gcctcaggaa?25980

gggccaagct?tgttttgttt?ttcacatctc?tgaatcctgg?ctccttagat?agtgatcaga?26040

aaaatatttg?ctaaaacaat?gtctcccaaa?tatgctggga?gaaaaaaagg?atgtataagt?26100

tgggtacaag?gtttgagaac?atattttcac?ttcaaagata?atctaaaaac?aaggataaac?26160

attcaagatc?atgagtagcc?actgtctcaa?cactggcact?aggctttcac?tgctgcttct?26220

tcagctgtgt?gaagatcccc?ttcaggccaa?atgtccttgt?ggcacactac?acacagcata?26280

agtttcatgg?tcattgtaaa?agaaagagta?aaaaataaag?ggaatttgaa?tcgaccatat?26340

ggcaatacag?gcatggcatg?catattcaaa?agccaatagc?ctaacagcca?ataccatata?26400

tgtactttat?tatatgcaag?tgctatatgg?gtcctacatg?tgtagtacaa?tttgcaaaca?26460

tttgttagca?gtaaatataa?ttgtaggtat?gcaatgtttt?tccattctca?tttccagcaa?26520

taactggttt?agaaaatcat?ttaatgaaga?tttcaataat?gtcaagatat?taaccttatc?26580

ttccaatgaa?caaaatggat?gacatctcag?taaaacttat?aagcctgtat?ttgaggaatg?26640

cttgctgtca?agtgttttgg?ttaggtatga?tgtctcatcc?tgaacttacc?aacaaggcct?26700

tgaagtcatt?aatgccctcc?tgcataacat?tactgatgag?aagaggcact?actcacagct?26760

tttattatca?ctgaagttaa?aatacagaaa?cacatttaaa?atggaattag?acctaaagct?26820

atttttttct?actgcaaaac?ctaaacatca?tctgtcacat?ggaataattg?tattcatttg?26880

aattttgttt?ttttttgtag?ttgtctttgt?atttaatttg?cagatttggt?ttatagtggt?26940

gtatgagcca?agaacataag?ggttttatat?ctagtttcat?gtctacagaa?tttaagtaac?27000

attatgaaaa?atacactctg?tacttctcct?ttcaaagagg?tcattacatt?acggtaaatt?27060

tgaaaaagtc?agtactaaag?ggtttttctt?aactactctt?tcaatcagaa?gaggtcacta?27120

gacaaataaa?aacatcaaga?taacacaaag?cttaactagg?taaagatttc?tctcttcagg?27180

gaattaaaaa?attccatttc?accacttgaa?gtcagtcttg?attgactaca?agactgctgt?27240

tatgtgatac?ggcaagatcg?tttagggaaa?aactaaaata?agaacttaat?tttttccatg?27300

aacatgagtt?ttaattgcca?tttttttaaa?aaattcaaat?ttattttatt?aatagataga?27360

tttggcccct?ggatactgcc?ccccccaacc?ttttattcaa?ctaggtttta?aatttttaaa?27420

cgcatataca?tggcaaaatt?tcaatctaaa?aaacgtaaac?gaagacacct?ccttccgcca?27480

gcccaaagcc?caagttctcc?tcactctgca?acacatcacc?ttgactcttt?catttaattc?27540

tgcaattatt?cactaagcat?ctctatatgc?caggtacagt?gtgggctatg?aggtgcagag?27600

atgagtaaga?caaggtattt?gcacttgagt?agttcactag?ggtggaaggg?aaaggcatta?27660

aacagataat?taaaatcctg?agtcctgaga?agaatgatca?aagtgtttct?actctgctgc?27720

ggtagaagag?attatcaaga?aaagcttcac?cagcattcaa?gtcagaactt?ggagaatatg?27780

tacaatttgt?tagatagata?agggtgagaa?agctttcctg?actgggtttt?ctttctcagt?27840

ggcaggattt?catccttagt?ggctggcata?ccaagtaaga?tgatcaaatt?taaattgttc?27900

aagatgctaa?ctacgatgtt?ttatttcatc?aggaaaataa?acataatacc?tctctgacct?27960

atttcatcat?ctgagctaat?caaatgagat?actgtacttt?attaacacat?ttggaaacga?28020

acataaatga?ttatataaac?acacagaatt?atcccatatg?ataaatggca?ttgtgccaat?28080

gtggttttta?ttcgtaggcc?accaaaggta?aacttcttcc?caaaagtagt?gacaaaattc?28140

cactgtagaa?tcccagacta?acagaaccac?atgaaacttt?gaatatcatc?taggcaattc?28200

agttctgtca?ttttattaat?gtagaaacca?aaacttaaga?aaagcaaaac?aattttaaaa?28260

attttaaaaa?gaaaaccaaa?aaaccaaaat?gatttataca?aatattctac?ccagattaca?28320

ggcggatgtg?aatcctcact?atattatcac?cagcccacga?gtgaaaccta?cgcaactatt?28380

tgctatacca?ctatccccat?gctaagtaac?cctgaacttt?aaagactccc?aggtggacct?28440

gatttggttt?agactcctac?agttttgact?cttctgcttg?atagcaaaaa?taagaaccaa?28500

atcccctgtt?taggaccttt?ctactacact?gtccaacttt?gtttccatgc?cccagtcttt?28560

aacagtgggc?atagctttct?taatcttgag?atgcacattt?ctctaagctt?tacatttcta?28620

aaatctgaat?acaatttaca?atcaaagtaa?aaagaaaact?ccagcctcca?gactgaaagg?28680

ttaagacatg?atgggttgtt?gtaacctatg?tatgtgcaaa?cttggctata?catagaaaag?28740

attacaagtt?gagtatccct?catgcaaaat?gctcaggacc?agaagtgttt?tggatttggg?28800

atttttttca?gattttggaa?tatttgcata?tacataatga?gacatcttgg?gaatgggacc?28860

caagtctaag?tataaaattc?attcatgttt?catatatgct?ttatatatat?agtctgaagg?28920

taatttaata?taatatttga?aataattttg?agcatgaaac?aaaggtcatg?ttaagtactt?28980

atgtgcagaa?ttttccactt?gtggcatcat?gttggtgtgc?tcaaaaggtt?ttgaatttca?29040

gattgggatg?tttgacttgt?attcacttca?ccatcactgt?aattatttgt?cttgatagct?29100

cccttgcaac?tataacttag?gttaaacaag?gatttcagtg?tgattcagca?ctaaaaggaa?29160

aagctactgt?gtacacagaa?aattatatca?gaaccatgcc?aggaaataca?attactagca?29220

gtgaaatttc?caaatattgc?agaataaatc?agaattttca?aagtttgcag?atgttagcat?29280

ggtgacagtt?agtaccaaag?gaagtgacat?gaggaaaaag?agacaacagg?acccttgggg?29340

ttattattca?tggtattata?gtatcggggt?aacaactctc?ggggtaacat?atcccaagtt?29400

gagatcttgg?ctcttggtcc?caatataaag?gatttccttg?gttgcctcat?ttcagtacgt?29460

ctcgaggtca?catatggaag?cactattaat?tctatctaat?gccagggcta?cccagggtta?29520

attcacaagc?ccatatgtct?tgctagaaaa?gctgagaggt?aaacagttgt?gtatagtatt?29580

aatatatgga?acagatattt?ctatcaccct?tgttaaagaa?ataaaaatta?gcaccgaaac?29640

cttgtcttcc?caggcttagt?gtgtcatcat?ctacacaacc?tacccgtagt?ctttttatgc?29700

atacgcttga?atactctttc?ctttttcaac?ccttgttact?ggccctctcc?agccttctat?29760

cacccatctt?cctccagttc?agagctcaac?tgaaatctct?ctttgaaatt?cactagcaat?29820

gcccttctgg?tcaaattcaa?tattcttttc?aaaacgtttc?aggatatgag?acagagtacc?29880

accctttctt?tattagtttt?tatatgacac?taaacttccc?aaacttactt?tgcacttggc?29940

cctttggtac?atctcagatg?tacatctcca?agcctcttgg?ccttttacct?gtgctccaag?30000

cttgtatttt?aactacatcc?aggaaacact?ctgcttggct?tacttatcta?tgcaaagtca?30060

agcagagtgt?tgtaatccag?ttttttcatc?actctgactt?tgctggtgat?gacccttatt?30120

ttcctcaccc?tacccactac?agcacaacta?tacttttctt?cgcagtgaga?gtatttccaa?30180

atattacaaa?catgtaccaa?caggcaagta?aaagacctaa?catgcacaat?gtcctttatg?30240

cagtttgctt?cactacagct?gaaagcagat?cacatcactg?ctggcaaagg?tgaaggcaaa?30300

agttggaagt?tatttaaaaa?aaactttcag?ggactaatgt?cagccccttt?tatcatccaa?30360

cctattcttc?taccccagtt?cttctgagta?atctgcctta?ccccttttct?ccattctcaa?30420

cacatgcccc?cttctcaagg?agacgtgtcc?tcttttctcc?ctcatccagc?tttggagtaa?30480

agcatactat?atagattctc?cttttctttt?tattaaatat?gttgcttatc?tctgtataca?30540

tggctaaaac?cctgacctcc?aattccctcc?agcctactat?cctaggtttt?gttcctcaaa?30600

atactcagtt?cttctcaatt?caaccctcct?ggggctacct?tgcagcagta?atatcaaagt?30660

aagcttgtca?aaatagagaa?caccatataa?tgtacataaa?attttcctct?agtccagata?30720

atatttcacc?cctgaattta?gggcatcaga?ataaacgcct?gatttttttc?cagataaatt?30780

ccatttactt?ctgccacttt?taaagaattt?aagatgcatt?gtttatcatt?taacccacat?30840

cacatcttaa?aagaacaggg?cactcccaaa?ttcacaagct?cttgtttttc?cacattatct?30900

tcattttcca?gtctcctagt?ttctatggaa?ttagccaata?taatgttaac?tgatatcaga?30960

gaaaacacac?taagaatagg?ctgcccaaat?ggcaagatgg?gatttaacag?ggtaactaat?31020

acaaaggctt?tcacttagat?tcgaaataaa?tcacacaagt?acagcataaa?gatctggtta?31080

gcagatctga?ggagtttaac?aacacatttt?agaagagtca?gagcctttaa?aaagtatctt?31140

ttaatccatc?aattctacta?cttacagttg?tctgaggaaa?caataggtga?gagcaaaaat?31200

ctaaacttgc?agatgttcat?tacagtattt?tatgattgaa?aacaacctat?gtgaatgaca?31260

atacaatgac?agaatgaatc?cttatacaat?cataaatgaa?agactatata?gccattaaaa?31320

ctggtatttt?agaagcatgt?ttaaggacaa?gggaatggtc?ctactactaa?agggcaggaa?31380

gtaaagctgt?atagtgtgat?tacaattaca?gtcctgtcaa?gtgaccttgt?ttttgttcca?31440

cttcaatgag?ttgaggggat?attttaatat?acagagcaga?tgtgcacact?ttgccttacc?31500

ccaggccctg?aaaagaaatg?gagaaacttc?tatgtctaaa?ggtgagtgct?aaaacaataa?31560

ccaaatttct?tatttcctct?caatctaagt?atgcttttac?acagtttctt?attagatttt?31620

aatttgacta?gtgggtaggt?attataagga?tatggtagtt?aagttgatgg?aactcagaga?31680

cagaaaaact?taagttaaaa?tcctatcttt?gccagtcagg?cactgagtaa?tcctgaggaa?31740

gtcacttaac?ttatttgaac?ctaaatttct?tcaacttact?tcctaaattt?ataacatact?31800

aacaaacagt?accaatctca?gaaggtttga?gggttaatga?aataacatac?atagaatact?31860

tagcacagtg?cccagcacat?aataaaatgt?tcaaaaatta?gtttatgcac?tttttcaaca?31920

agtatttctt?tggagctcct?attacgtgcc?agtctctggt?ctagatgcta?gacagagaat?31980

cagagctaat?gttgagacag?ctctggtagg?caatactgac?acagaacaca?atataaacca?32040

tatgcatata?caacagtgaa?tgttcatggt?acctatcagc?tctttctcct?tcataaatat?32100

tcatacagtt?tttcaacaat?atgactgaac?agacctggct?caagaacttc?actacagtag?32160

cagtaggcac?acacagaaag?tatattttca?gttccaaccc?aaattaacag?tgtagggaca?32220

cacccagtgt?gtatatgtaa?tatccctaat?aaataagtta?atatctaatt?agccataaaa?32280

tgttcatgct?ggaaggaata?tgaacagaaa?tatcagatcc?cagctccttt?agagatgaag?32340

aaacagaaat?gtcctaacag?ttacatcaac?ataatctaga?tttattccaa?aagtacacaa?32400

agaaaaaaag?gattacttga?taatctacag?tgatttccac?ccctactccc?cacaacccct?32460

cacgtaggac?aaaaccgaaa?atttcaacct?ttccctttgg?aaagcacgag?tggctgtagg?32520

agagactggc?ttggttgcac?agataataag?gtgtaataat?gaacgtaaat?gaaagtggct?32580

gatcatcctg?ggctagggga?atgacataca?aaacagaact?gtggtagaga?aggaactgtg?32640

gtaagagaag?gaagtggtaa?ccactcccag?ctgccattga?ctcggggcag?aggagagcaa?32700

tacctgggcc?agcaaacagc?gaaagatctg?ttggagccac?agttgaagaa?atgaactgat?32760

ggtcctgggc?agttagtaat?tttagaagca?gaaagcaagg?cctgaacacc?ttttctcaga?32820

acacaacagt?gaatgtaacc?tgtgtaggaa?gaaagaaaaa?acctttagga?ggatagagat?32880

aattaggatt?gagattcctg?ccctcagatt?cacaatgcag?agaacacacc?actgataaat?32940

gatgatgcaa?agtgcacaga?tcagaggaca?gaaaagggag?atttctctga?aatatgacac?33000

ctaaactaag?acttaaggaa?agctagtgaa?gaaaggaaag?tcattttagg?tagaggatat?33060

acaaaaacat?tgtacaaaag?atgccaaaat?aaaagtttga?gccaggtgtg?gtggcacgca?33120

cctgtagtcc?cagctatttg?ggaggctggg?gcacaaggat?cacttgagcc?ccaggagttt?33180

gaggctgcag?tgagccatga?tcaggccaca?gcactccatc?ctgggcaaca?gagtgagatc?33240

ctgtctcaaa?aaaaaaaaaa?aaaaaaagaa?agaaaacagt?aagggagttt?ggcagtttag?33300

gtgatgtaaa?caaaaacaaa?aaaactgata?aaattcaaca?gctattcatg?atttttaaaa?33360

atcttagtaa?actgataaaa?ttcaacagct?attcatgata?tttaaaaatt?tcagtaaatt?33420

gcagaattta?aaaaaaattc?tgaaataatc?agattaaata?aaaggcataa?aagtaggcat?33480

tacatttaat?gttgcatgac?tgtcattttc?ccttgaaatc?acaaataaga?aagagatatc?33540

catcactact?tctcaacatt?gtattagaag?tctgagtgta?gtaagtcaga?aataaacaaa?33600

aggaagatag?actggaaaga?cacagaacta?tcattacttg?cagaggacaa?ctatgtacat?33660

ggaaaatcca?aaagtgacct?acagatcaac?tattagaatc?aattagtcaa?tctagcaagg?33720

tcactaatat?aaggttactc?actataccaa?aaaaaattaa?attaaaaaat?cattcttaaa?33780

ccagtaataa?atagaaaacg?ttttttaaaa?atctaaaaac?taggaataaa?cctaacaaaa?33840

gacaggtaaa?gacctctgca?gagaaagctt?aaaaaatatt?acttattgat?agaaattaca?33900

aaggagataa?aataaaattt?taaaatgtat?ttataaatgg?agaaaagtga?caagttccta?33960

actggaagat?tcaatactgt?aaagaggtca?atattccata?aagtgatctg?tagattcaat?34020

aaaatcaaat?cagaatcccc?acagggtttt?tttattcagt?gggaactgac?aagttgattc?34080

tgaaatttat?atggaaaaac?aacatcgcaa?gaataaccaa?agcaatcttt?gaaagactta?34140

acactactcg?atatcaagac?tcctaacatc?ataataatta?agacagtatg?gtaatggcac?34200

aaggacaaat?gggcaaacag?aacagagatt?acagagaaac?agaccctcac?atatacaacc?34260

tcttgattta?tgatgaaggt?gattgtacac?tgggggaaaa?aaggttttac?caataaatgg?34320

ttctgagtca?accagatatc?cgtattttaa?aaataataaa?aatctcatac?cataataaat?34380

aaccaactcc?agatacatct?caatgtgaga?ggtaaaacca?atcttttaaa?tgaaaacaca?34440

ggaaaacatt?tttaaaacat?ttgggtcaga?aaaagtaagc?aaacaggatt?ctaacttaaa?34500

gcaaaaaatt?gaaggccggg?cacggtggct?cacgctgtaa?tcccaatact?ttgggaggcc?34560

gaggcaggca?gatcacctga?ggtcaggaat?tcgacaccag?cctggccaac?acggtgaaac?34620

cccatctcta?ctaaaaatac?aaaaaaaaaa?aaaaaaatag?ccaggcgtgg?tggcagatgc?34680

ctgtaatccc?agctacacgg?gaggctgaga?caggagaatc?acttgaaccc?aggaggcaga?34740

ggttgcagtg?agccaagatc?gcgccactgc?attccagcct?gggtgacaac?agtgagactc?34800

cgtctcatct?gaaacattca?tctcccttgt?caaacaaaat?accaaagcaa?agcagttaaa?34860

ttgtggttgc?agtctcctag?aagaacacag?ctgaattgaa?ccaagcaagg?acagaaaagc?34920

ccaccaaaag?gaaggagctt?ttgtattatt?tctatatttg?catttttata?atatttttaa?34980

tcattaaatt?ttggactccc?ttggagccta?aagatataag?catctagtgt?tgactgaact?35040

cctttcaggg?aaacatttgc?cctttgagac?taaactatgt?gtatatgaaa?acttaggctt?35100

gagatgtact?gtaaccaagc?taataaagtt?ttcagacctc?aaaatctaca?tgccgagact?35160

tggcattagg?aatatgggtt?tccaattgct?ggtagcattg?atacagtagc?atcatggcta?35220

ctgaagaaag?tggggggttg?gttattaaaa?gataaggatc?tatcaggctc?agaggcataa?35280

gggtcttgat?gttatttata?ccttggataa?ctgatgatac?aacaccgaag?actatcttgc?35340

agaattatga?aatctatatg?taagtcaata?atcactagtc?tctagataat?agtttagaat?35400

ggttcacagg?tgattatact?catttcttcc?ataagatttt?cctttttccc?agttacagag?35460

actaagctaa?atcagatgga?agcacccaat?tgcttagggc?aactacgcta?tttcctcagg?35520

gacacaccat?ctgtttgcaa?tgcacagcta?attctgagcc?tgttggtcct?cgcagagttt?35580

tcccttaaga?cttctgcctg?atgcctaaaa?tcccttaaaa?ctcctccctc?ctttcccttc?35640

tcccatggta?aggcaagagc?aggctggatc?tgacaaaact?taaatgatag?atgagatcta?35700

cataaaatac?ttatgtggcc?tttttttttt?tttttaagaa?taaagtgaag?aaacaattat?35760

gatcatgggg?agaaagaatg?tgagagcaga?aaggctcaag?tttatacatg?catcgaaata?35820

agagggaaga?aaacaaaagg?acaatgcacc?atggaaagaa?ggaaagcaaa?ataatggaaa?35880

gggagaaaaa?aggagcatct?cttcctagga?aagtaatcta?caatgctgtg?ttaatctgcc?35940

aacgctttgg?tgggactggc?aatcagaaat?tgtctttcct?cactgacaaa?catgaccaga?36000

ctctggcccc?tgatttgtaa?tttttttccc?aaatgtaaaa?tgagacaaaa?taactaaaac?36060

tactttaact?tgtttatttt?gataaaataa?ttatatataa?ttattgttga?aggaaatcta?36120

caatacacaa?tcttgggtgt?ttttatttaa?atctatcaca?cattgaataa?caaaattaaa?36180

atgtcagttt?ttcaactgga?gaaagtactc?aaatcaacaa?ccacgtgctg?aacaaagaga?36240

cccaattaga?gcacattata?gtttgatttg?gaaatgaata?catcaagcaa?aaaataaaaa?36300

acccatacat?atatcgtgtg?cttgcataca?aatgaaaggg?cagttgctgc?ttttctatct?36360

ctgtatgtct?tttcaagttt?aactctatcc?tccatgttca?gtgctcccaa?atatctatat?36420

tagtcctagt?ttctcgcaga?aaaagccatt?cgtttttgcc?ttttccctgg?ggacctattt?36480

gtaattcaat?gcatatttaa?gaatcttata?atgtagaaat?gtaacaggat?gcctgaagaa?36540

ggtgtcctag?aactataaat?atacactatt?atgtaatcag?tgaggtttac?acctaggaaa?36600

tctagatgga?atggttttcc?tgaagcaaat?gaacaaaaat?aaggaggttc?agtcttggtg?36660

gtgagaacaa?ggaaacactg?gaacagacct?gaagtagtac?agcaactgca?gaaaaaagga?36720

aaagtgaatc?cttacaaatc?atgagtgata?aacccgaatt?gttcacttta?tttttcaatg?36780

gcccatgtac?aaagacttct?ataaaagctt?ctgctcaaga?acagagagaa?gcttgttttt?36840

cccaatgaaa?tcagaatgct?tctaaccaca?gaatgccctc?atgctaatgt?acgtgcctat?36900

cttttccatg?aatactggga?ttactgtgag?accagtacag?tagggccaca?ctctcagata?36960

agtgtggtct?ctcctaaagt?aatcattccg?aacgtccatt?actcagaaat?gaagcagttc?37020

ttcaaacaag?aaacccaagc?aaagacactc?tggatcttac?tgacttgcac?ctgtttgaag?37080

gtaaatgtct?ggctctgcct?ttggtagcag?tactctgatg?aagtgtatca?aatggagaca?37140

caccaaaaga?taagggcatg?agaaaaatgt?ctttgtaagc?cagactaaat?agtttcatgt?37200

tgctctctat?tcattatcct?ccagctttta?gcaaagcttg?atttaaatgt?cctagcctta?37260

catcagctgt?tccattggca?ttagggaaag?actaatgtgt?tcatacttgg?atcagagact?37320

taaactggag?aagaaagatg?gaggcagcag?cactaaattg?aaccctcaat?acgtgttaaa?37380

ggggaagcct?cagaacaaga?atcagattat?tgccagatcc?agcaataacc?ccttaccact?37440

tggagattct?ccctgtatga?caatcttggc?atttggggct?ccactttatt?aaggaaggtg?37500

gcagtctcct?catgaattct?cgataggcaa?tgagatctat?gcaaattatc?agtcttcctt?37560

acttgccttg?gttaccagaa?aactcagagc?taagtattgt?gttcaacttc?taaagctttc?37620

ctcagctaaa?cttacggata?attgttctct?ttttctttcc?ctttttgact?tactgattct?37680

tatcttttgt?ggtcagtaga?tttggtctta?ctgaatttgc?tattatttca?agcttccaaa?37740

atcctttttt?ggaaaatgac?caaaataaaa?gccaatcaat?ggataaacta?acttttctcg?37800

tataatacag?gagcaacaag?atactgctca?tcttgaagcc?atgaatccta?gggatattta?37860

gactatattt?ggctaaaacc?agtaagcaag?gaagcttgga?ttatgcccaa?aagtacagaa?37920

ttttagagga?gaaacagagc?ttagagataa?acaagtccga?cctcctacct?aatgtaagaa?37980

attccttcta?caatttctca?gacagaaggt?tatctagcct?ctgcctgaat?agttccaggg?38040

tgacagggaa?catactacct?tacaatgttc?cattttgaca?gctatggtag?agagtcattc?38100

cttacattga?gctgaattct?gcctttcagt?ctaccaatta?attctagttc?ttcattacac?38160

agacatgtat?ttcttctttc?agaagacatt?ctttcactta?tttaaatata?taataattcc?38220

cctttattga?acacctactg?gtgtcaggct?atgtactaag?tgtaaatact?actgtacact?38280

atcttcacaa?cgatcaggta?aattaggaac?tatcctcttt?tgaaaagtga?gtcacagata?38340

cactgattag?actctaatta?cagccagata?tgttggtgct?tatatactac?tcctataaac?38400

aaatatttca?ttaaatttct?gacaaccaag?tcacatgaat?ttaatctgcc?ttcaaaactg?38460

aaagaaaaac?ttaagttaga?tcaatccaaa?tagaaaaaga?gagatggtct?agggatacaa?38520

ctgcaccagt?gtttggttca?ttgagaaaaa?caacaggaaa?agcatttaaa?aggatagcca?38580

tcagggagct?ccaggagata?gtaaagctga?cacctgtaac?atcagcaacc?atgacctgag?38640

gcctaggccg?caagcaggaa?acttcctctc?ttttatctca?gccaagaacc?acactcccaa?38700

aagatcaaac?gcattactgc?agagaaagca?gcactgtctg?aaggttaatt?tcaatacaac?38760

cagaagatca?caagtaattc?tgaatatata?catctttact?aagagaggtg?ggggaaaaat?38820

agcatgaacc?tgcaaaacag?gaaagaacca?tatcccagca?aacggaccag?gactccagat?38880

acaagctagg?acttcagggt?ctaaataaaa?actccattta?aggtagcgtt?ttaggacact?38940

agaatcctcc?tacccccaaa?agagaaagac?agagagagag?agagagaata?tgaggtgaat?39000

gctagatgct?agtagccatt?tctttgctta?aggtgctctc?ccatttccaa?ctaggttcca?39060

ttttttttta?atctttgctg?actactgagc?aattttattt?ggctaccttc?acctcaaact?39120

caacatgctt?aaaccagaat?tcgtctcccc?ttaatcctcg?tgccaaatta?ctcattaagt?39180

taaaggcatt?atccagccta?aaaaagcttg?gagtcattct?tttttctttc?atggagtcac?39240

tctgaatttc?tgtactccac?ctctttacag?ctaagaccta?ctgccactca?acaaatattt?39300

actgagtgcc?taggatgcac?caggcacttt?ccatacactt?gagatacatt?agtgaacaaa?39360

acgaagacat?ccactttcac?aaagcataga?atgataggaa?ggagacaata?aacagtaaat?39420

aagtacatat?gataagtaaa?taaatacagt?atgttagaag?gtattgttac?agagaaggaa?39480

agcactgtag?gatgatgaca?atattttaaa?aggtggcagg?ataagcctca?ctgagaaaaa?39540

ggtgtcatct?gagcaaagac?ttgcaggagg?tgagggagga?agccatgcag?gtatgtgagg?39600

gaagagcaca?caagcaaggg?aacagccaca?cacaggccct?actactaatt?cctctgattt?39660

ctttgtttca?aatgtcatac?agtcaccatt?tcaccccgtt?ctcaatgcca?tcaaaccaac?39720

tgggtagcca?ccctgatcca?ttccctctgc?ggcacaatta?gacattcttt?ttccacatta?39780

aaaccactct?cctgattttc?aaggcccata?attctctgag?cccacccttt?acaccatgaa?39840

cttccatttc?tcctcttaga?aatcctgaaa?cttagaatgc?tctttctcca?cacatgccat?39900

cctctccagc?caagaagtgc?ctcctttcca?ccacacatcc?actcaaagcc?ctatcctcct?39960

gcaaggcaga?gagatcaagt?cctacctcct?ctgtaaagca?gtccctgtgg?ttgctagtac?40020

tgagtctgta?gtcatatttc?ctcagcatca?attttttcaa?aagcaagact?gcctcttact?40080

tttcctatat?ttctcatcat?gttgatcact?actaaatatt?tgctaagaat?agatgagcta?40140

tttcctctgt?aaactgaagc?tctttcctct?gtaaactgaa?gctgtttgtc?aatttaaaca?40200

cttttattag?ctttcataaa?ctgctgaaat?agaatgatta?aagaatggtt?tgttgctgtt?40260

tttttgtttg?tttgtttttg?ttgagatgga?gtttcactct?gtcgcccggg?ctggagtgca?40320

gtggcgcaat?ctcggctcac?tgcaaactcc?acctcctgag?ttcaagtgat?tctcctgcct?40380

cagcctccca?agcagctggg?attacaggtg?cctgccacta?cgtccagcta?attttttgtt?40440

atttttagta?gagacagggt?ttcatcatgt?tggccaggct?ggtctcgaac?tcctgacctc?40500

gtgattcgcc?cacttcggcc?tcccaaagtg?ctgggattac?aggtgtgagc?tactgtgccc?40560

agcccaagaa?tggtttttta?tactcaaaaa?aaaaaaaaaa?aaaaaaaaaa?aaaaagcatg?40620

ggtgcaggat?atgccaaatg?ttaataatgg?ctggtgatgg?tttttttcct?ttctctaata?40680

caaattttca?gtcctgtgct?tatgtaactt?ttagaagaaa?agaatttgct?atgaatatat?40740

gtataaatca?atacaaatag?taagtgatca?actatcactg?gactcgtcag?gaagattcaa?40800

attacctaaa?aatataatgt?taaagaaaga?ctgttagtat?ctgaatggcc?tgcagttgca?40860

aagaaatagt?aaaactgtaa?tcaaggcaat?ctgaagcaaa?ttctcatggt?ttgcaaaaaa?40920

gggaaaggaa?actttcctgc?tgaagtggct?ctaacaatgt?atttactcta?tatgaaagga?40980

gcatggacgt?acgtgacccc?atcataagta?gaggagcatt?tgtataggaa?aagagtacat?41040

accctggagt?gcttaactga?aggctccacc?tttcattaac?agcataactt?cagtttcctg?41100

gtctataaaa?tggaaacaaa?gagggtcttc?tttcatagat?atgaactagg?ttccaatctg?41160

agcaaaattg?tgtcaattct?gcctgcccag?gcagatgggg?tttatggtaa?tacaaaatca?41220

tttgagtctc?agtggctgaa?ctactgttag?tctacatctg?tgccattcaa?agcagtgtct?41280

ttcttttata?tatatattta?cgattagacg?atgaaaaaat?actaacacct?ttggataatg?41340

tttagagttg?aaaagaatct?tggggtagag?ccgatgttat?caaaacctac?agttatcttc?41400

tgagcactgg?tcacctgtat?ctgggaacaa?atgggcttaa?gagtttggaa?attaagcagc?41460

aaataagtaa?gaagttttgg?tactctatac?aactaccatt?caaggttggt?tatgagaact?41520

aaatgatgcc?gtattagcca?tggtcaaaga?aaaaaaaaga?gagaagagag?aattaaacga?41580

gacaagacag?atagaatatg?tagcatattc?ttgcaaccct?tcaagaaatt?tcaaagcaac?41640

ctgtgtgtat?actttgcaag?tcaatttttt?ttaagttaga?ttagaaattg?ttctttgagg?41700

gagcagcttt?ataaaagact?tgatctgatc?tataaaattg?gaccataaaa?ccaactgaac?41760

ttagtccact?agtatttaag?aaagtgatgt?ctgagatgaa?taattacaag?tctaccaacc?41820

aattttcttc?atgatgaaga?agggtagcca?taagaaactt?acctggaaag?caaacaaaac?41880

acataaaatt?ggatctaatt?cagagtggta?aacaatttta?atgtttatgg?agactgcctg?41940

gatttgacat?tgagaaaatt?cagctaagaa?tggcattaaa?tgtaatccta?agtattggag?42000

ttaggctggg?tcaaaactga?ccataaattc?tgagaagact?ccaaaacttt?tcctcaagct?42060

agttctatgg?gacaaagcat?taaaaaatcc?ctgagaaata?tgccagcatc?tgccctcaat?42120

tccaaaagca?ggaagcaaag?atgtgaccca?atcacatgat?atcaaaccac?agtccatctg?42180

ttcagagaac?tctgtgttac?gtaagccatg?accaaggaag?aactgcaaaa?ggcaagaggt?42240

gtgtcgacat?ttgcaagggg?ctctgtggtt?tgaagagaca?cgttctcaca?tcagaagggc?42300

catccatagg?ataatggcat?tttcaaaatt?ccatttatta?cacatgaaca?tatttggtgc?42360

aataaaatga?cactacaaga?atggtgttga?gtccctgtaa?ctgctcaact?aaggcctaga?42420

accttttgac?aggggtcttc?cctacatgag?cggccctcct?cacaggaaca?agatttatct?42480

tcctcttgat?tatttttatg?tcaattcctc?tcttaatttc?aacaacaaag?cggatcatct?42540

aatattctaa?accaaagcct?tctaactaca?ccccaattca?attaactgta?cttactcaag?42600

accatcttcc?aaactactat?aggcctactt?ttctcaatca?ataagtatat?accaggtcct?42660

tttatcagca?attaaaaaaa?aattgacctt?ttccttgaga?actttaaggc?tttaatcatt?42720

ccccctccct?tccaccttta?gaattcactt?ttcataaatt?ctgtgaagtt?caaggcctac?42780

ttcacttaag?gaagtcactc?atcccttcgt?ggatgccaac?cacctatccc?aaccctgtcc?42840

cactcccacc?tccaagtcct?tcacatttta?aagcaccata?tagggcacaa?gatatggaat?42900

cagaaaatca?aagttcctgt?ctctgttctg?cccctgtgcc?accctaagaa?attcacctga?42960

gtcgtttttt?catctgtaaa?ttgaagtgat?aatatactta?ggacttccac?catttgaatg?43020

cctagtccta?ctgggcatcc?cataatgtta?ttctccctca?ctcattccac?tttgattact?43080

tttatgtttt?gtttccagct?atgtactata?gcttttagga?ttggggaaaa?aatgatagag?43140

gttaatacat?ccaaattcca?cagtacagaa?taaggaacct?aactctgaag?agtaacttgc?43200

cagtcagtca?gtaaaagcct?tgtttcctcc?cttggagtag?gccccaggac?agttggggac?43260

acaacttcaa?aagaactttc?acactcatca?aatccccctc?tgaattctac?ccacccttca?43320

aagtcagtgt?aagtcctaaa?gtgtccaaga?agcctccccc?aatcattcca?gcttacacta?43380

atcatttccc?tttttgaata?ctaatgcctc?cctatagaaa?tgatattaaa?aatatttaac?43440

aactggcact?acaagggtac?caaccaatca?gaaaggatgt?ttaaccaaaa?cacacatggc?43500

ccagtgggaa?ctgcttattg?aacatcagtc?ctgctcttta?gcaacaacac?agaatagcaa?43560

cctcaaactc?aaataccact?ttctcatgtg?atcttcacaa?tctcatgaat?taggcaaaag?43620

taggtattgc?cccattttct?gcataactgc?tggtgaaggt?aggacaaata?accaattgct?43680

ttcaacacgc?catacaactt?ttcctgatta?tttatacgga?attacaagtt?aatattgcat?43740

aaactggact?tacataaaac?agtataaata?ttaaaggaat?gctcaaatag?aaatcaacaa?43800

gcatttatgt?ggaatagaat?ataaaacaca?gtgctaagtt?ctgaggccac?aaaagaaaga?43860

aatggcatga?atcttgtcct?ctgggtacct?ataacgcatt?caagtagagt?taagtagcag?43920

cacaggcagt?agaaatggac?aacacaaact?gttaagtgtt?gcagagttct?ggaagacaaa?43980

gaattcaaga?actaaaccag?cacaggaagt?cagggctgag?aacttctcgc?actcccaaaa?44040

aaaggggcaa?aactaaatgt?gtagtgaaaa?ggctgaacag?tcaggagtca?gtgagaaaga?44100

gaaattgctc?gaaggtctgc?agtaatgaga?aatgagatcc?ctggtaggat?actcagagat?44160

ggccccaatc?ataagctgct?aagtgttgtt?ctaagtgctg?aatacaaatg?ggaaatctta?44220

taaaccttca?cggggaaggc?tgaggaagat?tagtttggca?gtagccatag?aaaagcctag?44280

atgagaaaaa?catgggaaag?caactagatt?tggaggataa?caggcaggat?taagctgaag?44340

gctgcatacc?aagaaaggag?gagacattca?agaggcattc?atagaagagt?tggattgggg?44400

gcacgttttc?aaagaaaaaa?agttatgaaa?tggcagaaag?gaagcaaata?gcattctcag?44460

atgggatata?catatagaca?tagtggtact?aaactgtgca?ctagggataa?ggaatcaatt?44520

tccctagaga?aacctatgtt?ggagacagaa?gttgggcaga?gaacattaaa?acatactcag?44580

aacataaaaa?ggtgcaagtc?tttaaaaggg?aagccaagtt?acagaggaaa?taaaaagcat?44640

ttgacctttt?tcagaatgtt?ttttaagggt?ggactgaggc?atcatcataa?ccaacagggg?44700

aggcagacaa?gctgaggcag?tctgggctta?gagtaataag?cacctggaca?gctttgtatt?44760

ttgtgcatac?catggagact?gtaaactcct?ccaggacatg?gactgagcaa?tgttctgtgt?44820

cttcaactaa?gtccactact?gttacttgaa?tacatgaacg?cttcttgtgc?tacttctggt?44880

ggaaaagagt?gcactgtgtt?attcaagtta?atagcggtgt?ggaaatgtta?cctgtgtttc?44940

atgcctaact?atactgattc?tcccaaatgt?ccacacagtt?atcctgcctt?cctccctagg?45000

ccaatgtcaa?aaatccattg?tttcctctaa?tgcaggccca?cgtgaaggga?ctcaacaatg?45060

tgctaagagt?cggaatgaag?cctatctgat?actcaaatca?tgaggacaga?atccaaagtg?45120

gataataaag?accaattgct?catcagacga?ctgaagaaga?aaaatgggct?acgccagata?45180

gtatgatgta?tacatattta?tatatatata?tgacatacag?gtttgggaaa?ctgagatctg?45240

agtgaaaatc?ctagctttag?cacttaagtt?attgggtact?taacgtgtct?gtaccccact?45300

ttgcacatct?gtaaagtggg?gcaaatgcca?ctactcctgg?gagtttactt?gtggtgatta?45360

aataatgtaa?ttatacaata?gtgtatgcat?ttacatcgta?gtaatgcaca?atacatagac?45420

ggtagctatt?aggactgatt?ataatcgtca?ccgtcagtct?tgatttttta?aaaaaatttc?45480

aacatctttt?gtccagtttc?agaaacagaa?atgtactttc?actgcatttt?agttgctaac?45540

actgaggctg?tgtattttag?cttctagtgt?ctcagttcag?ctgctaacga?agtttttcac?45600

tcatcccttt?gtggatacca?accacctacc?ccaacctgat?ttactatttt?gaaaaatcca?45660

gccaacagtc?ttccttgaaa?accagctata?cagatgtctg?aatcaaacta?ttaactgtca?45720

ctcaagaaaa?ggaacaacgt?gagtgatgtt?ccttcgagga?aataaaaagc?gtttaatcaa?45780

ttcacagtcg?ttcccaaaat?ttccaaaacc?cgcagaatga?gcaaacgttc?aagtttccac?45840

tatgaaaaca?atccgtagcc?gtctggttac?tggactcact?tcaacactcc?ccagacgcac?45900

gaaagaagaa?acattccgcg?catctccgcg?cttccttctt?ctcacacaaa?gcccccctgg?45960

ctggaggagc?agccccttcc?agcagggtcg?gctcgggtcg?agccgggcgg?gagtcagggc?46020

ggcctgcgga?cccaggggtc?tcaccacacg?tcgcccccga?ctcccactgg?acgaagccct?46080

agaggctcgg?agctcacacc?ccgcccggga?gccgccttcc?accccaacct?caaaccccgc?46140

cccgggttcg?gcagcctctg?gcacggaccc?tcttggggcg?ggggtcccca?gaacaaggtc?46200

acgccgtgcc?cagggggcgg?cggcgggcag?ccacggctct?gccagtcccc?gccggcctcg?46260

cactctccgc?ccctggccct?cgcccactca?caccccagag?ggcagccccg?gacctcggac?46320

gactccgccc?gactccacct?ccccggggag?tcccgagcgg?ggcggcctcg?ggcagccgga?46380

cacgtccgcc?cgcgcccgga?cacacgcccc?tgccccgcct?ccgctccccg?cttgcggttc?46440

gcccggcagc?cgccgagccg?cgcggcgcca?cgagagcccg?gcccgggccc?cggcgccgcc?46500

acctgcgccc?ccggccccgc?gccatgtttg?agaaagagca?ggagcgagcc?agaggccggg?46560

tccggcccgc?gcgccccgca?gtcgcccgcc?cgccgcgccg?ccgctcaccc?gtcgcccccg?46620

ggagcagcgc?cgccgccgcc?gccgccgccg?ccgccagcac?gaggaggagc?agccggggac?46680

gcggagcagc?gaccgccgcc?tccatggtcc?cgccgccacc?gcctgtggcc?cggcccggcc?46740

cggccgcgcc?gctgcctcac?cccagcaaac?ctcgcctcgc?cccacctccc?tagccgccgc?46800

ggcggcctcg?ctccggccct?ttgtaactgc?tcggaggacg?cgcgtccatt?ggctgccggg?46860

ctcccgccgg?ccccgcctcc?ccgccgccgc?gagctgccaa?gcgggaccca?gccgggagcc?46920

ccgcctgcgg?gcccgccagg?cagccaatcc?gcagccgcga?gcgccggttt?ctggccacgc?46980

cccacgctcc?ccgggggctg?ggccgccaga?ccccagcccc?ggcccgatcg?gctcccggct?47040

ccgagaggcc?gcgtgggggc?ggggtctgcc?agccccagca?ccgctcagcc?gctagccccg?47100

gagggccggg?tagagcgatg?ggtgtgtctg?tgtgagtctc?tttcggaaaa?aggctgtggc?47160

cgttcgacgc?tcttttcttc?taacctcctc?taggcgcgga?agatctggta?ctgcctcagc?47220

cccaccctga?ccccattcac?agctccgcat?tggcaatccc?agcacatgcc?acccagatcc?47280

gctgcagcgc?caggcccctg?catccacttc?aacttcccct?ctccaagtcc?acgcatcaac?47340

ttcagcattc?ccccgaagat?ccctcctcag?tgcccttcac?atgcgactca?ctctcctatt?47400

tcctcctgct?cccagcggtc?accccaaacc?cagctccccc?acccagttcc?aaacccagaa?47460

agtcctcaga?tcccagcgtc?agacccagat?cctgagccca?aacacacccc?caaatagcct?47520

cccgcctccc?tccagcacag?atccaggatg?gggatccaag?ccgcactcct?ctcaaacccc?47580

ttcccgatcc?aggttggaaa?gggaggatcc?ccaccccaac?ccctcaaagg?aggggttccc?47640

ccttcttagc?acccagctcc?cgcggggcgg?agggggagca?gtcatcatta?ctttgagctg?47700

tgtctgacac?tgctgtataa?taatcctgag?gtgtcactaa?aaacccaaat?aaactctacg?47760

ttttcattct?gaattcctaa?tttactgcga?gacgctccac?ccaccttccc?tctgcgacgc?47820

caaaatgagc?tccagatttg?taattcttcc?tgtcagacta?gtcctttctt?cagacacaaa?47880

cacagccaag?gaggctgtta?cgtagaacag?agaatatttt?tccgcagaac?cttttaagga?47940

ggaaatttta?ttttctgtgt?catttgagct?tagaattaaa?taaaccttga?tagcaggaat?48000

cagaatggtt?ctgattaatg?ccaatttgtg?cactacttta?gagtcactgg?gtgagcattt?48060

tccccacctg?tgaaggcttc?cttccgggag?atgaaaaggg?aaaaggcgtg?gatattggag?48120

ctgggatctg?agacccgcgc?gctttctccc?tcctgtctag?gacacttact?taagcaagtc?48180

agctaacctt?tctgaacctc?caacaggctc?agaggcctgc?aacttgctct?acaccgcagc?48240

tccagcagcc?tcagcagcaa?actcccctct?tgctcaggct?gagggattcc?agagagatgg?48300

cttctggcag?gctccagtcc?caatttgccc?tctcagttcc?agtttcttca?atggagattt?48360

ggtggacttt?gtgccacctg?aggtccctag?actgcctttt?tgctgctcta?tttgcaatgt?48420

ctttcataag?ataagagcta?atgagatttt?tattgtatga?atgaatgaat?gatctcagaa?48480

agtgactgtt?tttctctggc?cattagcttc?ttcatctcta?aaatgtaaat?aataatagta?48540

cctaccccgt?ttataaataa?aagggattga?atcacttgtc?ttgggcccct?taaatgacgt?48600

aatgtgtctg?gtacagtgtc?tggaacatag?taaatattta?gctaatgcca?tttctttgcc?48660

catccccttc?cagctctgta?tgattctaat?cagcatgtat?gttcatgtca?gtctgtgcct?48720

ttgacgtacg?gagcctagat?taatcagtgt?taatcacacc?tccagttcct?taaca 48775

Claims

1, a kind of have with SEQ ID NO 1 or SEQ ID NO 2 or SEQ ID NO94 or SEQ IDNO 95 or SEQ ID NO 96 comprise the oligonucleotide of the sequence that the subsequence at least 80% of 8 to 50 nucleotide bases is consistent and stand-in, variant, salt and the optical isomer of described sequence, it is characterized in that wherein said sequence can with comprise coding TGF-R or TGF-R _IIThe transcription initiation of gene opening code-reading frame or the zone of terminator codon or for " ring " or " projection " and be not the coding TGF-R or the TGF-R of part secondary structure _IIThe fully hybridization of mRNA zone.

2, a kind of SEQ of having ID NO 1 or SEQ ID NO 2 or SEQ ID NO 94 or SEQ I D NO95 or SEQ ID NO 96 comprise oligonucleotide and stand-in, variant, salt and the optical isomer of the subsequence of 8 to 50 nucleotide bases.

3, oligonucleotide according to claim 2 is characterized in that it is to be selected from the group that comprises SEQ IDNO 3 to SEQ ID NO 93.

4, oligonucleotide according to claim 3 is characterized in that it is to be selected from the group that comprises following sequence:

SEQ?ID?NO?3： 5′-CAGCCCCCGACCCATG-3′

SEQ?ID?NO?33：5′-CAGCCCCCGACCCATGGCAG-3′

SEQ?ID?NO?34：5′-CAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?35：5′-CAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?36：5′-CAGCCCCCGACCCATGG-3′

SEQ?ID?NO?41：5′-GCAGCCCCCGACCCATGGCA-3′

SEQ?ID?NO?42：5′-GCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?43：5′-GCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?44：5′-GCAGCCCCCGACCCATG-3′

SEQ?ID?NO?49：5′-AGCAGCCCCCGACCCATGGC-3′

SEQ?ID?NO?50：5′-AGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?51：5′-AGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?56：5′-GAGCAGCCCCCGACCCATGG-3′

SEQ?ID?NO?57：5′-GAGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?62：5′-TGAGCAGCCCCCGACCCATG-3′

SEQ?ID?NO?73：5′-ATGTGAAGATGGGCAAGACC-3′

SEQ?ID?NO?74：5′-ATCTCCATGTGAAGATGGGC-3′

SEQ?ID?NO?75：5′-AACGGCCTATCTCGAGGAAT-3′

SEQ?ID?NO?76：5′-AACATCGTCGAGCAATTTCC-3′

SEQ?ID?NO?77：5′-AATCCAACTCCTTTGCCCTT-3′

SEQ?ID?NO?78：5′-AAACCTGAGCCAGAACCTGA-3′

SEQ?ID?NO?79：5′-AGGGCGATCTAATGAAGGGT-3′

SEQ?ID?NO?80：5′-AGTGCACAGAAAGGACCCAC-3′

SEQ?ID?NO?81：5′-ACACTGGTCCAGCAATGACA-3′

SEQ?ID?NO?82：5′-TTCCTGTTGACTGAGTTGCG-3′

SEQ?ID?NO?83：5′-CACTCTGTGGTTTGGAGCAA-3′

SEQ?ID?NO?84：5′-CAAGGCCAGGTGATGACTTT-3′

SEQ?ID?NO?85：5′-CACACTGGTCCAGCAATGAC-3′

SEQ?ID?NO?86：5′-CTGACACCAACCAGAGCTGA-3′

SEQ?ID?NO?87：5′-CTCTGCCATCTGTTTGGGAT-3′

SEQ?ID?NO?88：5′-TCAAAAAGGGATCCATGCTC-3′

SEQ?ID?NO?89：5′-TGACACCAACCAGAGCTGAG-3′

SEQ?ID?NO?90：5′-TGATGCCTTCCTGTTGACTG-3′

SEQ?ID?NO?91：5′-TTCCTGTTGACTGAGTTGCG-3′

SEQ?ID?NO?92：5′-TTCTCCAAATCGACCTTTGC-3′

SEQ?ID?NO?93：5′-GGAGAGTTCAGGCAAAGCTG-3′。

5, a kind of pharmaceutical preparation, it is characterized in that it comprise at least a according to the described oligonucleotide of arbitrary claim among the claim 1-4 with and stand-in, variant, salt and optical isomer and/or at least a antisense compounds and at least a pharmaceutically acceptable supporting agent, vehicle or thinner, described antisense compounds is to be selected to comprise carrier and/or at least a the hybridization in coding TGF-R or TGF-R that allows to transcribe antisense oligonucleotide _IITarget nucleic acid and suppress the group of ribozyme, external guide sequence (EGS), few enzyme and the shot-catalyst RNA or the catalytic oligonucleotide of its expression.

6, pharmaceutical preparation according to claim 5 is characterized in that wherein said pharmaceutical preparation is infusion solution or the solid substrate that is used for continuous release of active ingredients.

7,, it is characterized in that wherein said pharmaceutical preparation is suitable for topical administration to brain according to claim 5 or 6 described pharmaceutical preparations.

8, a kind of at least a according to the described oligonucleotide of arbitrary claim among the claim 1-4 with and stand-in and variant and/or at least a antisense compounds or be used to promote the injured nerve path successfully to regenerate and the functional purposes that is connected again according to the described pharmaceutical formulation of arbitrary claim in the claim 5 to 7, described antisense compounds is to be selected to comprise carrier and/or at least a the hybridization in coding TGF-R or TGF-R that allows to transcribe antisense oligonucleotide _IITarget nucleic acid and suppress the group of ribozyme, external guide sequence (EGS), few enzyme and the shot-catalyst RNA or the catalytic oligonucleotide of its expression.

9, a kind of at least a according to the described oligonucleotide of arbitrary claim among the claim 1-4 with and stand-in and variant and/or at least a antisense compounds or be used for prophylactic treatment according to the described pharmaceutical formulation of arbitrary claim among the claim 5-7, treatment prevention and treatment nerve degeneration, after wound/wound, blood vessel/anoxic, neural inflammatory and infection back central nervous system disorders and age institute's inductive neural stem cell are upgraded the purposes that reduces, and it is characterized in that described antisense compounds is to be selected to comprise carrier and/or at least a the hybridization in coding TGF-R or TGF-R that allows to transcribe antisense oligonucleotide _IITarget nucleic acid and suppress the group of ribozyme, external guide sequence (EGS), few enzyme and the shot-catalyst RNA or the catalytic oligonucleotide of its expression.

10, purposes according to claim 9 is characterized in that it is to be used for inhibition and rise or enhanced TGF-R and/or TGF-R _IITGF-R and/or TGF-R in the disease that level is correlated with _IIExpression.

11,, it is characterized in that wherein said and rise or enhanced TGF-R and/or TGF-R according to claim 9 or 10 described purposes _IIDisease that level is relevant or described nerve degeneration illness and neural inflammatory conditions are to be selected to comprise following each sick group: Alzheimer's disease (Alzheimer ' s disease), Parkinson's disease (Parkinson ' s disease), storehouse Jia Shi disease (Creutzfeldt Jakobdisease, CJD), the neomorph of storehouse Jia Shi disease (new variant of Creutzfeldt Jakobsdisease, nvCJD), HallervordenSpatz Disease (Haliervorden Spatz disease), Huntington's disease (Huntington ' s disease), multiple system atrophy (MultisystemAtrophy), dull-witted, Frontemporal Dementia (Frontemporal Dementia) or other motor neuron illnesss, amyotrophic lateral sclerosis (Amyotrophic Lateral Sclerosis), spinal muscular atrophy (Spinal Muscular Atrophy), spinocerebellum atrophy (SpinocerebellarAtrophy, SCA), schizophrenia, affective disorder, severe melancholia (major depression), meningoencephalitis (meningoencephalitis), bacillary meningoencephalitis, viral meningoencephalitis, the central nervous system autoimmune disorder, multiple sclerosis (Multiple Sclerosis, MS), acute ischemic/anoxia-induced apoptosis (acute ischemic/hypoxic lesion), apoplexy, the central nervous system trauma of spinal cord of unifying, head and vertebra wound, arteriosclerosis, arteriosclerosis, microangiopathy dementia (microangiopathic dementia), binswanger (Binswanger ' disease) (leukoaraiosis (Leukoaraiosis)), retinal degeneration (retinaldegeneration), cochlea degeneration (cochlear degeneration), macular degeneration (maculardegeneration), cochlear deafness (cochlear deafness), acquired immune deficiency syndrome (AIDS) dependency dementia (AIDS-related dementia), retinitis pigmentosa (retinitis pigmentosa), vulnerability X-dependency is trembled/ataxia syndromes (fragile X-associatedtremor/ataxia syndrome, FXTAS), ophthalmic nerve nuclear paralysis disease (progressivesupranuclear palsy on the carrying out property, PSP), striatonigral degeneration (striatonigraldegeneration, SND), Nux Canarii albi pon cerebellum degeneration disease (olivopontocerebelleardegeneration, OPCD), shy dilatory person's syndromes (Shy Drager syndrome, SDS), age dependency lethe (age dependant memory deficit), dull-witted dependency neurodevelopment illness (neurodevelopmental disorders associated with dementia), Down's syndrome (Down ' s Syndrome), multisystem synapsin disease (synucleinopathy), superoxide-dismutase sudden change (Superoxide Dismutase Mutation), trinucleotide repeats illness (Trinucleotide Repeat Disorder), wound, anoxic, vascular disease, vascular inflammation, central nervous system is aging.

12, (a) TGF-R and/or TGF-R are disturbed in a kind of discriminating _IIBiologic activity or TGF-R and/or TGF-R _IIThe expression or (b) method of the compound that transmits of TGF-β 1/TGF-R signal, it is characterized in that said method comprising the steps of:

(a) candidate compound is cultivated with the test macro that comprises TGF-β 1 and neurone precursor cell; And

(b) propagation of active TGF receptor expression of calibrating or described neurone precursor cell;

Wherein

(c) compare with the described test macro that does not have described test compounds, (i) there is the candidate compound with the characteristic of wanting in the disappearance of the inhibition of active TGF expression of receptor or (ii) described neurone precursor cell inhibition of proliferation indication.